RM Global Health

Abstract
The National Institutes of Health (NIH) Trial to Assess Chelation Therapy (TACT) was begun in 2003 and is expected to be completed in 2009. It is a trial of office-based, intravenous disodium ethylene-diamine-tetra-acetic acid (Na2EDTA) as a treatment for coronary artery disease (CAD). A few case series in the 1950s and early 1960s had found Na2EDTA to be ineffective for CAD or peripheral vascular disease (PVD). Nevertheless, a few hundred physicians, almost all of whom advocate other dubious treatments, continued to peddle chelation as an office treatment. They claim that chelation dramatically improves symptoms and prolongs life in 80% to 90% of patients. In response, academics performed 4 controlled trials during the 1990s. None favored chelation, but chelationists repudiated those findings.
We have investigated the method and the trial. We present our findings in 4 parts: history, origin and nature of the TACT, state of the evidence, and risks. We present evidence that chelationists and their organization, the American College for Advancement in Medicine, used political connections to pressure the NIH to fund the TACT. The TACT protocols justified the trial by misrepresenting case series and by ignoring evidence of risks. The trial employs nearly 100 unfit co-investigators. It conflates disodium EDTA and another, somewhat safer drug. It lacks precautions necessary to minimize risks. The consent form reflects those shortcomings and fails to disclose apparent proprietary interests. The trial's outcome will be unreliable and almost certainly equivocal, thus defeating its stated purpose.
We conclude that the TACT is unethical, dangerous, pointless, and wasteful. It should be abandoned.

Executive Summary
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.

We investigated the social and the scientific histories of chelation therapy beginning in the 1950s. We examined TACT protocols and consent forms, which, in response to Freedom of Information Act (FOIA) requests, the NIH provided to us with curious redactions. We examined the existing RCTs and the numerous case series cited by the TACT protocols. We examined evidence for risks, including information that is not in the standard medical literature. We examined various hypotheses that advocates have offered to explain how chelation "works."

We present our findings in 4 parts. First, we provide a brief history of the use of disodium EDTA as a treatment for CAD. Next, we describe the origin and nature of the TACT. Next, we discuss the evidence for chelation as a treatment for CAD and for atherosclerosis in general, and place it in the context of other proposed treatments that have been ineffective after an initial period of enthusiasm. Finally, we discuss the risks. For each topic, we contrast our findings with relevant statements in the TACT literature, to the extent that such statements exist.

We found the following:

Most who persisted in advocating chelation after the 1960s have been outspoken advocates of other lucrative but implausible treatments, most notably Laetrile. In 1973 they created the American Academy of Medical Preventics "to promote the use of EDTA chelation therapy for cardiovascular disease." Later they changed the organization's name to the American College for Advancement in Medicine (ACAM). During the 1970s and 1980s, the editor of Chest and Archives of Internal Medicine called such advocates "pseudoscientific zealots"; the TACT protocols now describe them as "prominent experts." Several are assigned to trial committees, and nearly 100 have been employed as TACT co-investigators.
In about 1980, ACAM members began publishing, mainly in a journal of their own creation, case reports of chelation for atherosclerosis. Those reports and an unpublished report by a convicted felon are the main sources cited by TACT investigators in support of effectiveness. We examined those reports and found them not credible. One of the most prolific pro-chelation authors, cited at least 5 times in the TACT protocols, admitted under oath in 1997 to having falsified his data.
Since the mid-1970s, court documents and newspapers have reported at least 30 deaths associated with IV disodium EDTA, most of it administered by ACAM members. Nevertheless, not one death is mentioned in TACT literature, and the ACAM has long maintained that "millions of infusions have been administered over the last 30+ years, without any deaths being noted, when used in accordance with established guidelines." There is ample evidence of chelation morbidity, ranging from annoying side effects to life-threatening complications. An ACAM "Fellow" who belittles such risks has identified himself as a member of the TACT Data and Safety Monitoring Board.
In about 1990, the ACAM and one of its offspring, the Great Lakes Association of Clinical Medicine (GLACM), created "institutional review boards" (IRBs). According to the GLACM's Web site: "With an increase in the number of physicians who are under review from state medical boards for practicing alternative medicine, the IRB may offer protection." The GLACM IRB approved, among other representative studies, Henry Heimlich's "Induced Malaria Therapy" for HIV-positive subjects, conducted in China. In early 2000, with the GLACM IRB under investigation by the US Food and Drug Administration (FDA), both IRBs folded.
We present evidence that in late 1999 the ACAM, through its ally -- a powerful US congressman -- had begun to pressure the NIH to sponsor a chelation study. A proposal was overwhelmingly rejected by the Scientific Review Committee of the National Heart, Lung, and Blood Institute (NHLBI) in 2000, but a year later the NHLBI and the National Center for Complementary and Alternative Medicine (NCCAM) jointly issued a Request for Applications (RFA) for a chelation trial "expected [to] investigate the EDTA Chelation treatment protocol recommended by ACAM." The winning application -- the 2001 TACT protocol -- was approved a year later by an NCCAM "Special Emphasis Panel" that included an ACAM officer among its 6 members. He had been the chairman of the GLACM IRB mentioned above. The protocol that the Panel reviewed had named him as a participant in the trial. The protocol also conferred explicit benefits on the ACAM.
Early chelation investigators had chosen the disodium salt of EDTA, reasoning that if it could remove calcium from atherosclerotic plaques, it might shrink them. That notion was soon demonstrated to be invalid. It has largely been replaced by a "toxic heavy metals" antioxidant hypothesis, which is based on the potential for metal ions to produce free radical damage. Chelationists now cite "removing heavy metals" as the basis for their claim that chelation is effective for approximately 70 conditions, ranging from schizophrenia and autism to cancer. This provides them with numerous reasons to ignore any trial that finds chelation ineffective for CAD.
It is the "heavy metals" hypothesis that the TACT protocols present as plausible. Calcium-sodium EDTA, the form that is used for lead poisoning, would be consistent with that and less dangerous than disodium EDTA. Nevertheless, disodium EDTA is still the preference of the ACAM, which clings to the "decalcification" hypothesis even as it espouses the newer one. That is the stated reason that the TACT will expose subjects to the disodium salt, which carries the risk for acute, life-threatening hypocalcemia.
Biochemical literature, either not cited or misrepresented in the TACT protocols, has demonstrated that the heavy metals hypothesis is implausible. Antithetically, it also demonstrates that the chelation mixture used in the TACT has pro-oxidant effects in vitro.
The RCTs mentioned above, together with the early case reports and the biochemical considerations, constitute compelling evidence -- more compelling than the evidence against several other obsolete treatments -- that chelation with disodium EDTA is an ineffective treatment for CAD or for atherosclerosis in general. Chelationists have rejected such findings.
The TACT was thus begun in the absence of prior, supporting laboratory, animal, or human phase 1 or 2 studies, contrary to the usual requirements for a phase 3 trial, including those of the NIH itself. The NIH and the TACT principal investigator (PI) argued that there was a substantial demand for chelation, creating a "public health imperative" to perform a large trial now. The PI also argued that although several RCTs had been negative, "thousands" of positive case reports were at least as compelling. He asserted that the results of the TACT, supportive or not, would settle the matter and lead to rational practice. However, all evidence argues against those rationales: The demand is tiny; the case reports are not credible; chelationists have not changed their practices in response to previous controlled trials or other credible information; the results of the TACT are unlikely be either reliable or definitive.
In our opinion, TACT literature -- including 2 versions of the protocol, the consent form, information posted on the NCCAM Web site, and 2 editorials co-authored by the PI -- has misrepresented chelation, its risks, and the facts of the study. It has exaggerated the value of supportive case series, not only by ignoring evidence of bias and incompetence, but by misrepresenting citations and reporting erroneous data. It has minimized the dangers, both by understatements and by omissions of specific, published complications. It has not acknowledged the deaths mentioned above. It has repeatedly conflated disodium EDTA and a different drug, calcium-sodium EDTA. It has ignored accumulating evidence that antioxidant supplements similar to those used in the TACT are ineffective and possibly dangerous.
The TACT includes nearly 100 "chelation site" co-investigators who, in our opinion, are unsuitable to care for human subjects or to report trial data. Most espouse implausible health claims while denigrating proven methods; several have been disciplined, for substandard practices, by state medical boards; several have been involved in insurance fraud; at least 3 are convicted felons. Several were members of the ACAM or GLACM IRBs mentioned above. Few appear to have real expertise, required by TACT literature, in treating patients with CAD or in conducting clinical trials. Most continue to promote chelation while the TACT is in progress, contrary to good science, to human studies ethics, and to US Federal Code. The TACT consent form gives no hint of these points.
The TACT is to have multiple primary and secondary endpoints, including subjective "quality-of-life" outcomes. There are about 160 distinct study sites. Thus, by chance alone the trial will likely yield equivocal results, although prior evidence overwhelmingly points to chelation being ineffective for CAD. The most likely outcome of the TACT is that nothing, in the tiny subculture of chelation with IV disodium EDTA, will change.
We believe that the TACT violates numerous requirements of the Declaration of Helsinki. However, almost any journal to which the TACT investigators might submit a report must honor Helsinki, by virtue of its commitment to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, established by the International Committee of Medical Journal Editors. It seems that it will not be possible to publish a report of the TACT without overlooking Helsinki and the Uniform Requirements.
 

For those reasons and more, we conclude that the TACT is pointless, dangerous, unethical, and wasteful. It should be abandoned.

Introduction
The NCCAM and the NHLBI have funded a $30 million, phase 3 clinical trial of intravenous IV EDTA chelation therapy for coronary artery disease: the 5-year TACT.[1-6] Begun in 2003, there are expected to be approximately 2000 subjects -- each more than 50 years old and having had a myocardial infarction (MI) -- at "approximately 100 (now 160) research sites across the country...[that] will represent a mix of clinical settings--university or teaching hospitals, clinical practices or cardiology research centers, or chelation practices.[3]"

According to the protocol submitted in 2001, "TACT has been designed and will be conducted in collaboration with the American College for Advancement in Medicine (ACAM), the world's largest and most respected organization of physicians who employ chelation therapy.[4]" The protocol named several ACAM members, whom it called "prominent experts in chelation therapy," to the TACT Liaison Committee to the ACAM.[4] ACAM members are also on other TACT committees, and nearly 100 have been named co-investigators.[7] The ACAM currently has about 1000 members, of whom fewer than 800 are in the United States.[8] By comparison, there are about 800,000 licensed MDs and DOs in the United States. Not long ago, a distinguished medical editor, who himself had investigated chelation in its early years, characterized such "experts in chelation therapy" as "pseudoscientific zealots.[9-11]"

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,[12] and for those indications it has long been obsolete.[9] 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.[12]" Several deaths have been associated with unapproved uses of the drug by ACAM members.[13-20]

Prior to the TACT, 4 RCTs and several substudies of chelation for either CAD or PVD, involving 285 subjects, had been reported.[21-28] None found chelation superior to placebo. Nevertheless Dr. Gervasio Lamas, the PI of the TACT, argued that the trials had been underpowered to "exclude a small or moderate benefit of EDTA chelation," and that "case reports and case series encompass thousands of patients with successful outcomes...we believe a state of clinical equipoise exists and support a definitive trial [that] would...put to rest the lingering questions of efficacy....[29]" He asserted that "evidence [from such a trial], when widely disseminated, leads to changes in clinical practice, ultimately benefitting patients.[29]"

Both Dr. Lamas and the NIH have also asserted a "widespread use of chelation therapy,[2]" implying substantial demand among the "34% [of Americans who] reported using at least one alternative therapy in the last year.[4]" The late NCCAM Director Stephen Straus asserted that "The public health imperative to undertake a definitive study of chelation therapy is clear.[2]" Chelation, however, is received by considerably less than 0.01% of Americans each year. Even if the fraction were higher, it would not justify curtailing usual protections for human subjects. We shall discuss each of these points.

Contrary to the repeated suggestions of the NCCAM, the TACT protocol and consent form, and the ACAM, Na2EDTA is not approved for treating heavy metal poisoning.[1-3, 5,6,30] That approval -- which applies only to lead, not to heavy metals in general -- belongs to a different EDTA salt, calcium-disodium EDTA (CaEDTA Versenate), which does not carry the warning of acute hypocalcemia.[31] The rationale for Na2EDTA is that in the 1950s, when investigators proposed IV chelation as a treatment for atherosclerosis, they reasoned that if it could remove calcium from plaques, it ought to shrink them.[32]

Decalcification is no longer the favored purported mechanism.[33-35] The authors of the TACT protocols dismiss it, preferring a more sophisticated but still implausible antioxidant hypothesis that is based on chelation of heavy metals.[4,5] Nevertheless, the ACAM literature continues to assert the decalcification theory, and its "standardized protocol" continues to require Na2EDTA.[33,36] That appears to be the only reason that the TACT is exposing subjects to the more dangerous disodium salt.[1,4,5]

The trial also exposes subjects to "high dose antioxidant vitamin and mineral supplements" that are part of the typical chelation regimen given by ACAM members.[4,5] Among these are IV vitamin C at 7 g per infusion and oral vitamins E, A, and beta-carotene. The TACT will not compare chelation with standard therapies for CAD; all subjects are expected to receive standard medical treatments. The trial is a "2 x 2" design in which the chelation and placebo arms are each further randomized to receive either high or low doses of supplements.

The Timeline in the 2001 TACT protocol called for subject recruitment to take 36 months.[4] The TACT began to recruit subjects in the fall of 2003.[2] By the fall of 2006, only 1000 subjects -- half of the planned sample -- had been recruited.[37] According to ClinicalTrials.gov, the "expected completion" of the trial has been postponed to July 2009.[38]

Through FOIA requests, we obtained "redacted" copies of the original (2001) and 2003 TACT protocols,[4,5] the roster of the committee that approved the grant application,[39] and the June 2003 consent form.[6] Because the trial had already begun and because our initial FOIA requests were frustrated by delays and incomplete responses, we did not seek further revisions of the protocol or consent form, or other documents that are not available on the NCCAM Web site. It is possible that such revisions or other documents have addressed some of the problems reported here; it is also possible that the PIs have discussed some of these problems at meetings of trial committees or IRBs. We can only vouch for what we know, and we reserve the right to change our opinions if we become aware of new information that warrants such a change.

Nevertheless, "an experiment is ethical or not at its inception; it does not become ethical post hoc....[40]" Most of the problems we report were present when the trial began. Among them:

Substantial evidence that IV Na2EDTA is neither a safe nor effective treatment for CAD or atherosclerosis;
Evidence that the TACT was motivated by political pressure rather than by scientific or medical considerations[41,42];
The listing of a key ACAM officer on the NIH Special Emphasis Panel that reviewed the grant application.[39,43]
The enlistment of numerous "chelation site" co-investigators who, in our opinion, are unfit to be responsible for human subjects or to report data[7, 9-11];
The absence of mention, in the protocols or the consent form, of several known risks for both Na2EDTA and of the supplements used in the TACT regimen;
Citations in the RFA and the TACT protocols of several articles co-authored by a chelationist who had admitted, under oath in 1997, to having falsified his data[44]; and
The PI's inaccurate review of chelation case series.[4,5,29]
 

Dr. Lamas' favorable portrayal of the case series would have been necessary to convince IRBs that human subjects would be exposed to a substance likely to be effective enough to justify its dangers.[45,46] Because he granted that chelation has risks, he had to provide sufficient evidence of a therapeutic effect. All credible RCTs, however, had found no evidence of effectiveness; thus Dr. Lamas argued that "case reports and case series encompass thousands of patients with successful outcomes,[29]" implying that the case series nullified the disconfirming RCTs.

The TACT protocols' representations of the case series, however, are replete with errors. The protocols also ignore additional information, readily available from other sources, necessary for a thorough interpretation of those series. A comprehensive review of the case series -- which we provide in Part III of this article -- does not support chelation as an effective treatment for atherosclerotic disease. Rather, it agrees with the RCTs that chelation is ineffective, and indicates that it is more dangerous than the TACT protocols acknowledge. In our opinion it also suggests that the authors of most of the "positive" case series, including all of the large ones and all of those reported after the 1960s, have been biased to the point of fanaticism.

Scientific and ethical problems with the TACT have continued since its inception. Examples are the repeated conflations of Na2EDTA and CaEDTA, the appointment of a conspicuous advocate of chelation to the TACT Data and Safety Monitoring Board,[47] and the recent addition of several Canadian co-investigators who, we maintain, are also unfit for the task.[7,48] The PI has also continued to misrepresent chelation literature.[49]

I. A Brief History of EDTA Chelation for Cardiovascular Disease
Early Case Series
Beginning in 1956, a few small, uncontrolled case series reported that IV Na2EDTA seemed to have striking, beneficial effects on CAD, PVD, and cerebrovascular disease.[32, 50-53] By 1963 it became clear that those reports, which were based primarily on subjective outcomes, had been wrong. When followed for more than a few months, subjects with CAD had rates of death and MI similar to those expected for untreated patients at that time.[54] Two small series of subjects with intermittent claudication had also shown no evidence of improvement.[54,55] Several autopsies from various series had revealed no evidence of decalcification of plaques or reduction of plaque size. Within a couple of years, case series of IV Na2EDTA for cardiovascular disease no longer appeared in the academic medical literature.

Chelation Goes Private: "A Big Cash Cow"
Nevertheless, a tiny group of advocates continued to practice "chelation therapy," usually in the office. Then as now, it consisted of an initial series of IV infusions of disodium EDTA, magnesium, vitamins, and minerals, followed by monthly "maintenance" infusions. At first, chelationists called the treatment a "chemical Roto-Rooter" or a "chemical endarterectomy," but eventually promoted it as a near-panacea for conditions as disparate as multiple sclerosis, schizophrenia, autism, cancer, peptic ulcer, back pain, and chronic obstructive pulmonary disease.[34,56,57] According to a recent article reprinted on the Web site of the ACAM, the most conspicuous organization of chelationists, "heart patients undergoing chelation typically receive 30 to 40 weekly treatments, then are scheduled for lifelong monthly sessions to keep the arteries free of plaque.[58]" The article quoted the price of a single chelation treatment -- the ingredients of which cost a few dollars[59] -- to be $120-$125. In addition, according to the Trial Chelation Consultant for the TACT,[4] there are "nutritional supplements in the range of $20 to $200 per month [and] diagnostic study costs and professional fees...ranging from a few hundred to several thousand dollars.[57]"

The article on the ACAM Web site reported that TACT co-investigator and "prominent expert[4]" Allan Magaziner "said his center [was] treating 400 to 500 heart patients with chelation.[58]" L. Terry Chappell, another "prominent expert" and co-investigator, told a government hearing in 1999 that he had treated "at least 2500 to 3000 patients with chelation therapy" over a period of about 18 years, but that this represented "only 20-25% of [his] medical practice.[41]" Former ACAM president and convicted extortionist Ted Rozema,[60] also a TACT co-investigator, testified at the same hearing that in 16 years he had treated "over 2000 patients [with] over 80,000 infusions of EDTA.[41]" The 2001 TACT protocol states that Trial Chelation Consultant, prominent expert, and TACT co-investigator Dr. Martin Dayton, who was convicted of conspiracy and mail fraud in 1986,[61] "has clinical experience with over 75,000 chelation infusions.[4]" The late H. Ray Evers, a convicted felon revered by chelationists as a "pioneer of chelation therapy," reportedly claimed to treat, during the 1970s, 1000 patients per year at $3000 each.[62,63] According to a former practitioner, "chelation is a big cash cow.[59]"

The Rise of Activism-Based Medicine: Laetrile Spawns Chelation
In their early days many chelation advocates also favored, and some still favor, the lucrative quack cancer treatment Laetrile. Most chelationists still offer other dubious treatments, such as IV hydrogen peroxide, "detoxification," hair analysis, "antineoplastons," "live cell therapy," coffee enemas, "ozone therapy," magnets, homeopathy, and more, while denigrating the methods of modern medicine and public health, including surgery, pharmaceuticals, immunizations, fluoride, and controlled clinical trials.[7,64] By the mid-1970s, their activities had drawn the attention of the FDA, Medicare, state medical boards, professional ethics committees, and criminal prosecutors.[18, 65-67] In an effort to protect themselves, advocates established organizations, symposia, "certification boards," journals, political connections, lobbies, and -- a few years later -- political action committees, IRBs, and "Achievement Awards" (at times bestowed upon, presumably, unsuspecting recipients[68]).

Among such early organizations were the National Health Federation, which had been around since the 1950s and included, among its officers and board members, Drs. H. Ray Evers, Garry Gordon, Michael Gerber, James Privitera, W. Douglas Brodie, and Bruce Halstead -- all chelationists[69]; and the Committee for Freedom of Choice in Cancer Therapy (later renamed the Committee for Freedom of Choice in Medicine), founded by John Bircher and Stanford lab technician Robert Bradford who, in addition to smuggling millions of dollars worth of Laetrile, hawked filmstrips entitled Chelation Therapy and the Killer Diseases.[63,70,71] Halstead was the Committee's vice president. Each of these organizations was primarily concerned with protecting its members' freedom to peddle Laetrile.[69-73]

In 1973 chelationists established the American Academy of Medical Preventics (AAMP) "to help educate physicians and to promote the use of EDTA chelation therapy for cardiovascular disease.[34]" Among the founders, officers, and key members were the 6 physician members of the Laetrile organizations named above. Four of the 6 -- Evers, Halstead, Brodie, and Privitera -- were subsequently convicted of felonies.[62,67,69,74,75] The first AAMP president was Harold W. Harper, another Laetrile advocate.[75] When Laetrile sales were mostly forced underground by the US Supreme Court's decision in the Rutherford case of 1979[76] (the AAMP had filed an amicus curiae brief in opposition to the eventual decision[77]), chelation emerged as heir-apparent to the title of "most successful medical fraud in history.[78]"

In its early years the AAMP mounted one of the first "direct-to-consumer" drug advertising campaigns in the form of "An Open Letter to Those Persons Interested in Chelation Therapy.[79]" The letter suggested that chelation was better, safer, and cheaper than the mainstream alternatives:


All too often, the remarkable benefits available from low fat dietary regimes, in conjunction with megavitamin, chelation, and hyperbaric oxygen therapy are not offered to patients who may be facing needless vascular surgery, such as bypass heart surgery, or even amputation of an extremity (because of impending gangrene), or a future of continual pain and disability and eventual premature death, when frequently these alternative approaches could have provided as good, if not better results at less cost, and without surgery.[79]



The letter recommended a "filmstrip presentation with sound, suitable for showing to all community groups," which "is self explanatory and does not require a physician's attendance.[79]" The filmstrip appears to have been Bradford's Chelation Therapy and the Killer Diseases: The reader could buy it for $50 from the "Committee for Freedom of Choice.[79]" The letter exhorted readers to "become involved in one or both of the lay organizations that are attempting to increase the general public awareness regarding these new therapies": the Association for Chelation Therapy and the National Educational Society for Natural Healing.

The AAMP also hired a law firm to advocate for chelation.[80] Within a few years, AAMP members had founded the American Board of Chelation Therapy (ABCT), GLACM, and the American Preventive Medical Association (APMA).[34] In 1986, the AAMP changed its name:


The members of the American Academy of Medical Preventics (AAMP), recognizing that their training, experience, and clinical practice would form the basis for emergence of new medical paradigm, [sic] changed the name of their organization to the American College for Advancement in Medicine (ACAM).[34]



The ACAM now refers to itself as "the voice of Complementary, Alternative and Integrative Medicine.[81]" In 1988, the ACAM created the Journal of Advancement in Medicine, which has since published most of the pro-chelation articles.[82] In 2000, the journal's name was changed to Clinical Practice of Alternative Medicine.[83] The AAMP offspring have also changed their names: the ABCT to the American Board of Clinical Metal Toxicology (ABCMT), the GLACM first to the Great Lakes College of Clinical Medicine (GLCCM) and recently to the International College of Integrative Medicine (ICIM), and the APMA to the American Association for Health Freedom (AAHF).[84-86]

The ACAM "Industry Directory" currently lists American Biologics as one of its "Legacy Partners.[87]" American Biologics has marketed numerous quack products, including Laetrile.[70] It is owned by convicted Laetrile smuggler Robert Bradford, who founded it in the early 1970s.[70,71]

Later Case Series: The Parallel Universe of Chelation Literature
Reports of uncontrolled series of IV Na2EDTA for cardiovascular and other diseases began to reappear in about 1980. Unlike the original reports, these were written exclusively by advocates, all members of the AAMP/ACAM, and published, with 1 or 2 exceptions, in little-known, nonrefereed journals. Several articles reported sample sizes in the hundreds or thousands. Each series reported dramatic improvements in 80% to 90% of subjects.[34,57,88,89]

Complications, if mentioned, were described as minor. Rates of death from any cause, if mentioned, were implausibly low. For example, in a report of 2870 subjects, most of whom were said to have CAD (844 subjects), PVD (1130 subjects), or cerebrovascular disease (504 subjects), followed in Brazil for a 2-year period in the early 1980s, the authors reported 7 deaths; 2 were in the CAD group.[90,91] In a subsequent report, the same authors wrote that when chelation had been "administered according to the ACAM protocol," there hadn't been "a single reported incident of renal failure or death since 1960.[92]" As discussed in Part III of this article, the claim was false and the authors had reason to know it.[18,93,94] One of those authors, James Carter, is now a TACT co-investigator.[7]

Two reports were "meta-analyses" of the others, reporting more than 20,000 subjects and creating, for their statistical analyses, imaginary control groups "defined to have no improvement in cardiovascular capability.[95,96]" The first author of those reports is "prominent expert" L. Terry Chappell, also now a TACT co-investigator.[4,7]

One of the most prolific chelation authors is Edward McDonagh, DO, the author or co-author of more than 30 exclusively pro-chelation articles.[89] According to a reporter:


In December 1996, the [Missouri medical] board brought suit against McDonagh, alleging 13 counts of negligence and malpractice.

[The] state investigation of McDonagh's records revealed a pattern: Since the late '70s, he'd diagnosed patients without obtaining their medical records or recording the results of their physical exams. Other mistakes were charted on the racked bodies of former patients. In the 1980s, he misdiagnosed a case of gangrene, which festered until the patient fell into a coma and had to have his leg amputated above the knee.

The only consistent thing about his files was that each record had serious inconsistencies, argued David Meyers, a KU cardiologist who analyzed McDonagh's records for the board's initial case against the doctor. Meyers testified that McDonagh hadn't used orthodox methods to treat anything. In some cases, McDonagh's prescriptions and diagnoses ran contrary to existing medical knowledge.

On the witness stand, McDonagh argued that he had kept slipshod records, recording only positives about his experiments, to avoid possible liability lawsuits.[44]



That admission resulted in the following exchange between the board's attorney and Dr. McDonagh:


Attorney Bradford: "Do you think it weakens the validity of your conclusions as represented by your papers that you can't show your underlying data?"

Dr. McDonagh: "I think it might.[44]"



Despite such testimony, the administrative hearing commission found in favor of McDonagh. The opinion was upheld by a circuit court, but in 2003 it was "reversed and remanded" by the Missouri Supreme Court.[97]

A few years before that testimony, Dr. McDonagh had "failed to pass the Special Purpose Examination after the Board found probable cause to question his competency to practice medicine," and thus in 1995 the Missouri Board revoked his license to practice medicine.[98] He continued to practice, however, because the "Board action [was] stayed by court order on 1/17/95 while appeal was pending.[98]" In 1997 the Board reinstated his license "in accordance with a Settlement Agreement.[98]" McDonagh was the subject of a series in the Kansas City Star investigating his peddling of chelation to trusting, scientifically naive Amish and Mennonite patients.[99]

Chelation Gains a User-Friendly Hypothesis
As it became clearer that the decalcification theory was no longer taken seriously by medical scientists, chelationists sought new explanations for the putative effects of Na2EDTA, though never relinquishing the old one.[80,100] Several were proposed, among them platelet function inhibition, anticoagulation, lowering of serum lipids, and calcium channel blockade. The most popular one, which persists, was based on the removal of toxic heavy metals. Through the removal of iron, mercury, aluminum, lead, and other metals that, according to advocates, are toxic even at the miniscule levels found in most people, the panacea effects of chelation are explained.

Thus, proponents claim:

Chelation reverses autism by removing mercury introduced by childhood immunizations and dental amalgams.[101,102]
It reverses Alzheimer's disease by removing aluminum, copper, and zinc from the brain.[35,103]
It reduces high blood pressure, which "has been shown to be associated with increased total body burden of lead.[104]"
It prevents cancer because "the metals interact with the DNA, RNA, enzymes, mitochondria, and cellular components to contribute to the causation of diseases. The immune system appears to be effected [sic] to allow cancers already in the body to manifest into a diseased state.[104]"
It reverses atherosclerosis by reducing "free radical" production dependent upon iron.[105]
And more.
 


All in all, according to Elmer Cranton, a past president of the ACAM, one of the "prominent experts" named to the TACT Liaison Committee to the ACAM,[4] and author of Bypassing Bypass Surgery: Chelation Therapy: A Non-Surgical Treatment for Reversing Arteriosclerosis, Improving Blocked Circulation, and Slowing the Aging Process[106]:


The use of EDTA to restore the balance and distribution of essential metallic elements, while at the same time removing toxic heavy metals and catalytic free iron, has been shown to slow or arrest progression of diseases of aging. Other benefits of chelation occur from uncoupling of disulfide and metallic cross-linkages between molecules, by normalization of calcium metabolism, by reactivation of enzymes poisoned by lead and other toxic metals, and by restoration of normal prostacyclin production along blood vessel walls. Lasting benefits follow a series of intravenous EDTA infusions, plus nutritional supplementation and lifestyle improvements.

This well-documented, safe, and effective therapy deserves widespread recognition and acceptance.[105]



Removing toxic heavy metals has the additional appeal of parroting an approved use of the similarly named, but different drug: CaEDTA.[31] Chelationists and the TACT literature frequently conflate the 2 drugs, as in this statement posted on the NCCAM Web site: "When used as approved by the FDA...for treatment of heavy metal poisoning, chelation with EDTA has a low occurrence of side effects.[3]" Chelation advocacy organizations cloak their agenda in euphemism: The ICIM urges Web-surfing practitioners to "Check out our friends at ABCMT for more information about certification in Heavy Metal Toxicology[85]"; in 1998 the ACAM's phone number was 1-800-LEADOUT.[34]

Such explanatory sleight of hand has fooled not only patients, but regulators. After the recent hypocalcemic death of a 5-year-old autistic boy in the office of an ACAM member, the chief of the US Centers for Disease Control and Prevention (CDC) Lead Poisoning Prevention Branch mistakenly "determined 'without a doubt' that it was medical error, and not the therapy itself, that led to the death of [the] 5-year-old boy," because "'only Calcium Disodium EDTA should be used...No medical professional would ever have intended to give the child Disodium EDTA.[107]'" Similarly, the Pennsylvania Board of Medicine subsequently charged that the practitioner had "...used disodium EDTA to chelate [the boy] for metal toxicity which should be treated with CaNa2EDTA instead.[108]"

After the hypocalcemic death of a 53-year-old woman in Oregon in 2003, to whom a naturopath had administered chelation therapy in order to "remove heavy metals," the CDC reported: "The Oregon State Naturopath Licensing Board is conducting an investigation to determine whether Na2EDTA or CaEDTA was administered to this patient.[13]" The Oregon Board investigated and found that the naturopath "was medically negligent in performing a chelation procedure," but the order does not name the chelating drug.[109]

Curiously, the Oregon naturopathic formulary lists EDTA without a cation, adding, "Board approved certification required before therapeutic IV chelation is allowed.[110]" In 2003 such certification was likely to have come from the ACAM: The Oregon Naturopathic Board included, on its list of approved continuing education courses, an ACAM course entitled "Heavy Metal Detoxification.[111]" Thus, in our opinion it is virtually certain that Na2EDTA was the drug that killed the woman, and "therapeutic IV chelation" is a state-sanctioned oxymoron in Oregon. Would the Board have found the naturopath, himself an ACAM member, at fault for administering the very drug that its approved certification course had urged him to administer?

In each case, regulators missed the point and revealed their naiveté about fraudulent medical practices: These "medical professionals" almost certainly intended to give disodium EDTA, although there was no indication for any chelating agent. Each practitioner was, ipso facto, "medically negligent in performing a chelation procedure,[109]" not merely in performing it in an especially reckless way. In our opinion, no competent, ethical, medical professional would have given EDTA in any form.

Chelationists have also used the toxic heavy metals hypothesis for another purpose. Health insurers typically do not cover chelation treatments because of lack of demonstrated efficacy, so most patients pay out of pocket.[112] In order to collect payment from insurers, some chelationists falsely report that patients have toxic levels of heavy metals.[113]

The ACAM's "certification" organization is the ABCMT (formerly the American Board of Chelation Therapy). It is not recognized by the American Board of Medical Specialties. At the time of its creation in 1982, it offered this "Definition of Chelation Therapy":


A form of medical therapy designed to restore cellular homeostasis using various mechanisms including metal binding and restoring ionic balance. For optimal results Chelation Therapy should be complimented [sic] by utilizing other modalities such as nutrition and exercise.[114]



Chelationists have recently contrived to change both standards of care and third-party payments without having to resort to evidence. The ABCMT has implored all state medical boards to adopt its "Standard of Care for Increased Body Burden of Toxic Metals.[102]" This declares the ABCMT to be "the only professional organization with over twenty years of continual teaching, testing, monitoring results and seeing marked improvement in patients' symptoms with metal detoxification." It extols hair analysis and "provoked urine testing," and refers to "in office intravenous detoxification of documented toxic metals" without naming chelation per se. It "resolves" that "established detoxification techniques, which have been proven safe and effective over time, be employed to detoxify these patients.[102]"

In a "Cover Letter to all State Medical Boards" sent with the "Standard of Care" document in July 2004, Chairman Robert Nash wrote:


ABCMT is now ready to certify competence and assist in your concerns about patient and public safety.

Physicians who complete the toxic metals toxicology course and successfully pass the appropriate tests should be recognized as Physician Clinical Metal Toxicologists by each state's medical board.

If you have not provided us with a more thorough, updated Standard of Care within 30 days, we will conclude that our Standard of Care has been accepted.[115]



Nash is a former ACAM board member and is now, according to the abstract of a recent article by him, "on the Data and Safety Management Board" [sic] of the TACT.[47] Assuming that Nash is a member of the Data and Safety Monitoring Board of the TACT, he appears to have conflicting interests.

Nash was an "expert witness" called by chelationist Robban Sica, a TACT co-investigator who filed a federal lawsuit in 2004 in an attempt to prevent the Connecticut Bureau of Health Care Systems from disciplining her for numerous instances of substandard care.[116-118] In ruling against Dr. Sica, the federal judge wrote:


While most "mainstream" physicians would see Dr. Sica as treating, for example, cardiovascular disease with EDTA Chelation, Drs. Nash and Sica concede only that Dr. Sica was treating [heavy metal] toxicity....[119]



At least 1 state medical board appears to have been duped by the heavy metals ploy even prior to the "Standard of Care for Toxic Metals" project. In 2001 the Missouri Code of State Regulations added language about chelation. It begins with a promising statement:


...the board declares the use of ethylinediaminetetracetic acid (EDTA) chelation on a patient is of no medical or osteopathic value except for those uses approved by the Food and Drug Administration (FDA) by federal regulation.[120]



Notwithstanding that preamble:


The board shall not seek disciplinary action against a licensee based solely upon a non-approved use of EDTA chelation if the licensee has the patient sign the Informed Consent for EDTA Chelation Therapy form, included herein....[120]



The consent form warns that chelation "may be harmful" and "has been authoritatively demonstrated to be ineffective in the treatment of vascular diseases," (emphasis in the original) but also includes these statements:


My physician has explained to me and I fully understand:

(a) that the use of ethylenediaminetetracetic [sic] acid (EDTA) has been approved by the federal Food and Drug Administration (FDA) only for the use of removing heavy metals from the body;

(b) that the FDA has not approved the drug EDTA for treatment of diseases or conditions other than heavy metals poisoning;

...(i) that the Missouri State Board of Registration for the Healing Arts strongly recommends that Missouri citizens not undergo EDTA chelation therapy for the treatment of any human disease, illness, malady, or physical condition other than heavy metals poisoning;

Notwithstanding having read and understood the above, I hereby elect to undergo treatment with EDTA chelation therapy under the protocol recommended by the American College for the Advancement in Medicine (ACAM) [sic].[120]



It seems odd that the Missouri Board would warn citizens to avoid chelation, which it deems dangerous and ineffective, but declines to discipline licensees who push it. The Board appears to have been unaware, when it wrote that rule, that the statements about heavy metals undermine the statements urging citizens to refuse chelation, and are also quite false: The EDTA salt recommended by the ACAM protocol,[33] Na2EDTA, is not approved by the FDA for removing heavy metals.[12] Even the somewhat safer CaEDTA is approved for the removal of only 1 heavy metal (lead), not heavy metals.[31] Because there is nothing in the Missouri rule requiring a proper diagnosis of "heavy metals poisoning," chelationists can conform to the letter of the law by doing exactly what they've been doing for years: prescribing chelation ostensibly to remove heavy metals, no matter what may or may not ail the patient.

Several other state medical boards or practice acts have language addressing unapproved uses of EDTA or chelation.[121] They vary in the extent to which they tolerate or condemn the practice, but most appear to have been misled by the heavy metals gambit. Tennessee is a laudable exception.[122,123]

Statements that disodium EDTA removes toxic heavy metals suggest, at least in regard to CAD, that several unproven speculations are true: (1) that individuals are "poisoned" by trace amounts of ubiquitous environmental substances; (2) that these alleged poisonings cause atherosclerotic CAD; (3) that disodium EDTA safely and effectively removes these unnamed heavy metals; and (4) that it thereby reverses CAD.

Chelation Makes the "Top 10 Health Frauds" List -- Briefly
Despite their organizational efforts during the 1970s and 1980s, chelationists continued to be inconvenienced by regulators and criticized by influential physicians. Alfred Soffer, the Editor-in-Chief of both Chest and Archives of Internal Medicine, had performed trials of Na2EDTA during its early days and concluded that it was not useful for CAD or PVD.[55] In a series of editorials, he called chelationists "pseudoscientific zealots" whose practices were "an abuse of the physician's freedom of choice.[9-11]" Others referred to promotions of chelation as "the next generation of medical sleight of hand," "deceptive," and "pseudoscience"; to chelation itself as "fringe medicine," "scientific chicanery," "sham therapy," and a "medical fraud" with "all the classical hallmarks of quackery"; and to its practitioners as "super salesmen" and "modern quacks," who "rip...willing victims off for $3000 to $5000 for a few weeks of injections of EDTA.[63,78, 124-126]"

Chelation for atherosclerosis was condemned by the Medical Letter, the American Heart Association (AHA), the American College of Physicians, the American Academy of Family Physicians, the American Society for Clinical Pharmacology and Therapeutics, the American College of Cardiology, the American Medical Association, and the American Osteopathic Association.[127] In 1989, the FDA included chelation therapy on its list of "Top 10 Health Frauds.[128]" Within a few months, however, the FDA bowed to pressure from former AAMP President Ross Gordon to remove chelation from the list because of a pending "approved study" that was never completed.[34,129]

A Novel Role for IRBs
In response to such criticism, in the early 1990s the ACAM and the GLACM created their own IRBs.[34] The GLACM Web site explained the mission of its IRB:


With an increase in the number of physicians who are under review from state medical boards for practicing alternative medicine, the IRB may offer protection. The IRB recommends that any GLACM members who want to organize procedures in their offices and get peer-reviewed, officially-sanctioned research contact Karen at Dr. Chappell's office (419) 358-4627, to get guidelines for preparing a proposal.[130]



The GLACM IRB approved numerous projects eventually subjected to criminal, civil, and FDA actions, among which were "Evaluation of the Effect of the Immunotherapeutic Technique Enzyme Potentiated Desensitization (EPD) for a Considerable Variety of Illness/Conditions/Diagnostic Conditions," "Extracorporal Hemo-Infusion Therapy," "The Effects of DMPS (Dimercapto-propane sulfonate) in a Total Mercury Detoxification Protocol," "Insulin Potentiation Therapy," and "Gene-Activated Therapy (GAT) for Treatment of Cancer.[131,132]"

At least 2 projects involved the deaths of experimental subjects: The "induced malaria therapy for HIV" study conducted in China by Henry Heimlich, and the "DMPS Mercury Detoxification" study conducted by IRB member Paula Bickle, who had obtained her "PhD" from a mail-order degree mill.[133-136]

Another study approved by the GLACM IRB was exposed as a fraud after "Stimulated Autologous Immune Serum" was sold to a woman for $15,000 with the promise of "an excellent chance [that she] would respond favorably to the serum treatment and that it could effect a cure of her [ovarian cancer].[137]" A laboratory analysis subsequently found the "serum" to consist of "water, lactic acid, a dye substance, and no protein material.[137]" GLACM IRB member George Kindness was the president of the company, Amscot Medical Labs, Inc., that had manufactured the serum. According to a 22-count criminal federal indictment in 2003, Kindness "falsely represented to FDA investigators that he had an M.D. in general medicine.[138,139]"

In 1999 the FDA inspected the GLACM IRB and found multiple violations of federal regulations.[140,141] IRB members had voted to approve their own projects. Some projects involving new drugs were approved without having Investigational New Drug Applications. Several informed consent documents were found to lack "the basic elements"; the following examples are quoted from the inspector's report:

There is no statement indicating that the study involves research.
There is no description of the procedures to be followed.
Procedures that are experimental are not identified.
There is no description of any reasonably foreseeable risks or discomforts to the subject.
Exculpatory language is used through which the subject is apparently made to waive their [sic] legal rights.
There is no statement indicating that participation in the study is voluntary...
There is no description of additional costs...
[The] statement appears to suggest that this investigational therapy is superior to conventional therapies...
[The] statement...appears to suggest that this investigational therapy is safe.
There is no disclosure of appropriate alternative...treatment[s] that might be advantageous to the subject.[140]
 


Referring to "the IRB's written policies and procedures," the inspector wrote:


It appears that this document was written not for the purpose of having a relevant, functional, and useful document for the IRB's operations but more for the purpose of fulfilling a regulatory requirement for written procedures.[140]



In 2000 the FDA banned the GLACM IRB from approving new studies or admitting new subjects to ongoing studies. The FDA letter to the IRB secretary, L. Terry Chappell, concluded: "Based on the deficiencies found during this inspection, we have no assurance that your IRB procedures are adequately protecting the rights and welfare of the human subjects of research.[141]"

The FDA did not inspect the closely related ACAM IRB, but we believe that if it had the findings it would have been similar. That IRB's "Sample Protocol for Chelation Therapy for Arteriosclerotic Disease," updated in 1993, stated that the study's purpose "is to accumulate evidence to demonstrate the effectiveness and safety of chelation therapy for arteriosclerotic disease.[142]" It asserted that "3500 abstracts attest to the efficacy and validity of EDTA chelation therapy," but made no mention of a recent controlled trial failing to demonstrate effectiveness.[21,22] It recommended "self-selection" of subjects to receive EDTA after they had been told that it works. It did not stipulate real control groups or blinding, but recommended that patients serve as their own historical controls. It described mainly subjective outcome measures.

The Sample Protocol's Consent Form stated:


I understand that this project is conducted under the aegis of the Institutional Review Board ("IRB") of the American College for Advancement in Medicine ("ACAM"), for the purpose of establishing the effectiveness of treatment of arteriosclerotic diseases by intravenous ("IV") administration of EDTA with magnesium, according to protocol. The study will continue until this therapy is approved by the Food and Drug Administration.[142]



The Consent Form falsely suggested that the FDA had approved Na2EDTA for the treatment of heavy metal toxicities, and stated that for atherosclerosis the drug was "considered 'experimental' by most physicians." It referred to "persantin" [sic] as "experimental and unproven," thus implying that for treating atherosclerosis, "most physicians" would rate chelation at least as favorably as they rated dipyridamole (Persantine). The Consent Form required the subjects -- not the "treating physicians" -- to decide whether to consider standard medical and surgical therapies: "If I desire further information about these types of drug therapy, I will ask my physician...There are various kinds of vascular surgical procedures, and if I am interested in these I will ask my physician...I understand that all these therapies have certain risks about which I should ask my physician if I am interested.[142]"

Those statements and the following paragraph in the Consent Form illustrate what the FDA Inspector presumably meant when he criticized the GLACM consent forms as "exculpatory":


I understand that no compensation for participation in this study will be provided by Dr.________, his office, or the ACAM or the IRB, and I also understand that neither ACAM nor the IRB has a policy to medically treat or compensate for physical injuries incurred as a result of participating in biomedical or behavioral research. I understand and agree that ACAM is not a participant in the study and that the IRB merely serves as a reviewer and collator of the data produced under this study. I expressly agree, as a condition of my participation in this study, that ACAM and the IRB shall not in any manner be responsible for any physical injuries incurred as a result of my participation in the study and I waive, in advance, any claims against either and both of them [sic].[142]



In 2001 both the GLACM and the ACAM IRBs "ceased operations," citing FDA "requirements" and "restrictions.[143-145]" At least 8 former members of the GLACM and ACAM IRBs are now TACT co-investigators.[7] Two, Drs. Chappell and Ralph Miranda, are "prominent experts" named to the TACT Liaison Committee to the ACAM.[4] Dr. Chappell was also a member of the NIH Special Emphasis Panel that reviewed the original TACT proposal.[39,43] It is instructive to compare Dr. Chappell's opinion of the GLACM IRB[146] with that of the FDA.

Evidence-Based Medicine Weighs in
Meanwhile, in response to the tiny but shrill minority of physicians promoting chelation (the ACAM had fewer than 400 members in 1986), a few academic investigators performed RCTs. Between 1991 and 2002, four adequately designed trials and several substudies, involving 285 subjects, were reported.[21-28] These compared Na2EDTA with placebo for several objective measures of CAD or PVD. None showed an advantage for Na2EDTA.

Other authors have challenged the hypothetical mechanisms by which Na2EDTA was claimed to attenuate the process of atherosclerosis:

The dosing of Na2EDTA, although capable of toxicity in the short run, is far too small to effect a significant, lasting reduction of metallic free radicals or calcium.[147,148]
EDTA is relatively ineffective in removing mercury, iron, and copper, as contrasted with lead, because the former metals are more tightly bound to tissues and proteins.[147,148]
There is evidence of EDTA's paradoxical generation of reactive oxygen species in the presence of iron, and a possible augmentation of that effect by high ascorbate concentrations, such as those in the chelation solution advocated by the ACAM and used in the TACT.[147-150] Thus, "instead of protecting against and neutralizing metallic free radicals, EDTA in the presence of iron and ascorbate produces free radicals and potentially induces the changes that it is intended to prevent.[148]"
 


More recently, it has become clear that clinical trials of antioxidants, even of those that had shown promise for preventing and treating atherosclerosis in laboratory and animal studies, have been disappointing.[151] Thus well before the TACT began to recruit subjects, 2 experts in atherogenesis had called for a moratorium on clinical trials of antioxidants: "Instead, we should concentrate on developing the scientific base that will enable us to design an appropriate trial to test the oxidation hypothesis.[151]"

Chelavangelism Strikes Back
Controlled trials notwithstanding, chelationists refused to accept negative results, claiming that the authors had been dishonest because of "vested interest[s] in catheterization and surgery"; that the trials hadn't followed the "ACAM protocol" closely enough; that the results had actually been favorable to chelation; that one trial had been too long, another too short; and more.[57,94, 152-162] To counter the negative publicity of disconfirming RCTs in the 1990s, the ACAM posted "Consumer Information" on its Web site:


Chelation therapy is a safe, effective and relatively inexpensive treatment to restore blood flow in victims of atherosclerosis without surgery.

Every single study of the use of chelation therapy for atherosclerosis which has ever been published, without exception, has described an improvement in blood flow and symptoms. Adverse editorial comment to the contrary lacks evidence and stems primarily from physicians with a vested interest in catheterization and surgery.

Chelation therapy promotes health by correcting the major underlying cause of arterial blockage. Damaging oxygen free radicals are increased by the presence of metallic elements and act as a chronic irritant to blood vessel walls and cell membranes. EDTA removes those metallic irritants, allowing leaky and damaged cell walls to heal. Plaques smooth over and shrink, allowing more blood to pass. Arterial walls become softer and more pliable, allowing easier expansion. Scientific studies have proven that blood flow increases after chelation therapy.[152]



In 1998 the Federal Trade Commission (FTC) ordered the ACAM to stop advertising chelation as effective against cardiovascular disease.[163] Nevertheless, the ACAM continued to publish similar statements. According to its Position Paper on EDTA Chelation Therapy, posted on its Web site as recently as June 2003 and still posted on the HealthWorld Web site, "hundreds of doctors nationwide have successfully treated hundreds of thousands of patients with EDTA chelation therapy," not only for coronary and other vascular diseases, but for "dementia, cancer, arthritis and numerous other diseases...; it is a safe and effective treatment for atherosclerotic vascular disease, as it consistently improves blood flow and relieves symptoms associated with the disease in greater than 80% of the patients treated." It is not merely complementary to standard treatment, but "an effective first step alternative to surgical treatment for atherosclerotic vascular disease in most cases.[164]"

Most chelationists include promotional language on their own Web sites. Of the nearly 100 "chelation practices" involved in the TACT, about 80 have Web sites. Of those, at least 70 promote chelation.[7]

In 1997 and 2000, "complementary medicine" researcher Edzard Ernst authored 2 critical reviews of Na2EDTA for atherosclerosis, each concluding that the method "should now be considered obsolete.[165,166]" After the first review, chelationists L. Terry Chappell and John Wilson wrote an angry rebuttal to the editor of Circulation.[158] Dr. Ernst offered this response:


Regardless of what Chappell and Wilson state, chelation therapy is not based on good science.

A perhaps more important point relates to a repetitive pattern in the scientific investigation of "bogus" therapies. Proponents first manage to mobilize supporters to campaign in their favor. This brings financial gain. When skeptics ask about the evidence, the burden of proof is swiftly put on their shoulders, and the lack of evidence is made to look like a "conspiracy" of orthodoxy against the alternative. If scientists then decide to rigorously test the method, its proponents would celebrate this as a breakthrough for their method. Again, this amounts to financial gain. Subsequently, a study may prove that the method is ineffective. Proponents now claim that the research was flawed, did not adhere to their protocol, or was wrongly analyzed. The press coverage yet again brings financial gain. This pattern repeats itself with depressing regularity, e.g., when laetrile or Di Bella's cancer cure were promoted. I wonder whether chelation therapists are trying to play a similar game.[158]



That conjecture appeared in print in January 1999. Dr. Ernst was soon proven correct.

II. The Genesis of the TACT
From Health Fraud to "Complementary and Alternative Medicine": Activism Trumps Evidence
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).[41,167,168] 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.[41]"

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.[41]" Dr. Lenfant replied that there had been only 1 proposal to the NHLBI for a clinical study of chelation in the previous 30 years.

In February 2000, the NHLBI Advisory Council, chaired by Dr. Lenfant, rejected a new proposal for a study of chelation for CAD. The Council had apparently accepted, without question, the erroneous claim that "this therapy is currently being used by half a million people.[169]" Nevertheless, the Council judged chelation to have little scientific basis, deemed a trial to be too expensive ($24 million), and observed that:


...many patients who use alternative therapies may not be subject to a scientific argument of non-efficacy. It is unclear that any outcome would have an impact upon current clinical practice.[169]



Yet Rep. Burton seems to have been heard at the NIH. In the previous month, just as the FDA was completing its investigation of the GLACM IRB, the NHLBI had solicited "a market survey to assess the availability and technical ability of small business firms to act as the Coordinating Center in the conduct of a clinical trial to determine whether EDTA chelation therapy" is effective in patients with chronic stable angina.[170] Dr. Chappell, according to his curriculum vitae, provided a "consultation in Bethesda in March 2000" to the NIH.[43] In May 2000, the NCCAM's National Advisory Council for Complementary and Alternative Medicine approved the "concept" of funding a large trial of chelation, by a vote of 11 in favor, none opposed, and 2 abstentions.[171] One of the speakers during the Public Comment session of that meeting was Beth Clay, a staff member of Rep. Burton's House Committee on Government Reform.

In approaching the newly established NCCAM, Rep. Burton and the ACAM were surely aware that the Center's founding history and the charters of its advisory councils make it beholden to political and ideologic, rather than to scientific or medical interests.[172] After all, the American Association for Health Freedom, an ACAM offspring, takes credit for having been "instrumental in creating the National Center for Complementary and Alternative Medicine.[173]"

In the ACAM newsletter of May 2000, President Ted Rozema heralded the anticipated chelation study:


On a national note: a very large research grant application has now been made to the National Heart Lung and Blood Institute at the NIH for a 2,200 patient, 100 site study called the Trial to Assess Chelation Therapy (TACT). This application must first be scored and then monies allocated for it. This is a time-consuming and politically charged issue. We have wonderful allies in the person of Representative Dan Burton (Republican - Indiana), along with his great staffer, Beth Clay. His Government Reform Committee has been overseeing chelation therapy to see it gets a fair shake in research even though there are other elements that do not want studies done. Any assistance you can give Congressman Burton will be assistance well spent to make the playing field equal. Our lobbyist, Bill Chatfield has really been diligent in his opening doors for us to actually get to those in power who are so well protected by their staff. This is not an easy task, but after 20+ years of respect in Washington, Bill is able to do this job with great skill and effectiveness.[42]



Dr. Lamas Makes His Pitch
In the July 2000 issue of the American Heart Journal, Edzard Ernst offered his review of EDTA chelation therapy for CAD.[166] Noting that the literature consisted of numerous enthusiastic but uncontrolled case series countered by a few, exclusively negative controlled trials, Ernst again concluded: "The most striking finding is the almost total lack of convincing evidence for efficacy. Given the potential of chelation therapy to cause severe adverse effects, this treatment should now be considered obsolete.[166]"

In an accompanying editorial Drs. Gervasio Lamas and Alan Ackermann, soon to be named, respectively, the PI and the trial co-manager of the TACT, disagreed. Estimating that "more than 500,000 patients may" undergo chelation each year, they argued that:


Ernst and others have over-interpreted meager clinical trial data in coming to this conclusion...the randomized trials have studied fewer than 200 patients in aggregate...the absence of evidence of efficacy does not constitute evidence of absence of efficacy...case reports and case series encompass thousands of patients with successful outcomes...a small or moderate benefit of EDTA chelation cannot be excluded...patients with coronary disease have not been systematically studied...biologically plausible mechanisms of benefit have not been thoroughly explored.

...we believe that a state of clinical equipoise exists and support a definitive trial to measure the effect of chelation therapy on clinical and physiologic endpoints.[29]



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.[1]" 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.[1]" 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.[174,175] 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.[2] 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.[2]"

According to the TACT press release, "Over 800,000 patient visits were made for chelation therapy in the United States in 1997.[2]" That number was an estimate provided by the ACAM.[3] It included all visits for chelation, not merely those for CAD. Courses of chelation typically include at least 30 infusions given over 10-30 weeks,[58] so even if the ACAM number had been correct it meant that at most 27,000 people -- 0.01% of the population -- underwent chelation in 1997. This is about 1/20 of Dr. Lamas' estimate in the American Heart Journal, and a tiny fraction of the "34% [of Americans who] reported using at least one alternative therapy in the last year," later cited by Dr. Lamas as a justification for the trial.[4]

It was ironic that Director Straus cited a "lack of adequate prior research." The usual order of in vivo investigations of a proposed treatment is as follows: (1) animal studies; (2) phase 1 human trials; (3) phase 2 trials; (4) phase 3 trials, with the understanding that each step is contingent upon the previous one having suggested at least safety and, in the case of phase 2 studies, efficacy. That sequence is compelling for both ethical and scientific reasons, and is stipulated in part or in its entirety by pertinent treatises, including the Helsinki Declaration, the US Code of Federal Regulations, and the NCCAM's own policies.[176-178]

With regard to how chelation for cardiovascular disease fits into this scheme, the only relevant literature comprises the controlled trials cited above. They correspond, roughly, to phase 2 trials, but none has "suggested effectiveness of the drug" or shown "efficacy," as Federal Code and NCCAM policy stipulate prior to a phase 3 trial.[177,178] The trials have also revealed more than trivial risks, as discussed in Part IV of this article. Paradoxically, the NCCAM itself, in a 2002 statement of its priorities for 2003, observed that "premature efficacy studies" were scientifically unwise, even if it overlooked ethics and safety:


...the research portfolio would be better served by an increased emphasis on studies of the mechanisms underlying CAM approaches, and by more thorough examination of the interventions themselves, as critical preparation for, and to better ensure the success of, more substantive phase II and III trials.

Lack of adequately defined products or optimal dosage schedules risks that premature efficacy studies might fail, casting a pall over further research into otherwise promising modalities.[179]



The same document, published nearly a year before the first subjects were enrolled in the TACT, named "studies of the biology of EDTA chelation therapy in animal models" as a "FY 2003 Research Priority.[180]" By 2007, however, the NCCAM Web site had listed no such animal studies. Without commenting on that history, in 2006 Director Straus wrote in Science: "NCCAM now has a policy of requiring dose-range studies and other preclinical research before conducting clinical trials.[181]" His statement was in response to a critical article that had asserted, among other points, that the TACT is a wasteful project.[182]

The TACT press release made false statements about the drug to be investigated:


EDTA, which effectively speeds removal of heavy metals and minerals such as lead, iron, copper, and calcium from the blood, is approved by the U.S. Food and Drug Administration (FDA) for use in treating lead poisoning and toxicity from other heavy metals.[2]



The NIH Special Emphasis Panel that approved the TACT protocol included L. Terry Chappell,[39] whom the protocol had named as a participant in the TACT.[4] This is curious in light of the NIH policy on "avoiding conflicts of interests during scientific review group meetings," which should have required Chappell to "be absent from the room during the review.[183]"

The TACT press release revealed that NHLBI Director Lenfant, who had stood his ground at the meeting of the NHLBI Advisory Council in 2000 despite having been browbeaten by Rep. Burton,[41,171] had finally capitulated to the pressure. In so doing, he seemed relieved that the NCCAM was taking primary responsibility for the TACT: "NCCAM's leadership in initiating and supporting this study is to be commended.[2]" At a recent meeting of the NCCAM Advisory Council, however, "Dr. Kirschstein explained that because heart disease is a key focus at NHLBI, the [TACT] grant will be transferred to NHLBI after the review by the data and safety monitoring board on February 23, 2007.[184]"

Chelationists: From Pseudoscientific Zealots to "Prominent Experts"
According to the August 2001 protocol, which is the application that the NHLBI and the NCCAM must have originally approved, the PIs and ACAM members had been jointly planning the TACT since well before the RFA was issued. Charles Hennekens, the trial co-principal investigator, "was the recipient of the 1997 Prevention Award from the ACAM.[4]" Drs. Lamas and Hennekens each had "a longstanding interest in rigorously testing the most plausible small to moderate benefits of chelation therapy in cardiovascular disease," and "accordingly, in early 1999, collaboration was initiated with a multidisciplinary team...that includes experts in alternative medicine, specifically chelation therapy....[4]"

The 2001 TACT protocol cites the ACAM protocol as its source for the TACT treatment regimen.[4] It cites the "ACAM's protocol and safety information," without rigorous justification, as its sources for "absolute contraindications" and for assurances of safety.[4] It cites the ACAM's formula for dose adjustments on the basis of creatinine clearance.[4] It requires every "Clinical Unit" to have at least 1 senior investigator or "chelation practitioner sub-investigator" who "must have formal training and certification by ACAM in chelation therapy, and must be approved for participation in TACT by the ACAM Liaison Committee.[4]" It assigns ACAM members not only to the ACAM Liaison Committee, but also to other key committees, including the Operations Committee and the Publications Committee.[4]

The protocol names, as Trial Chelation Consultant, Martin Dayton, MD, DO, "the former Director of the Scientific Research Committee of the ACAM.[4]" It names Dayton and other "prominent experts," including the aforementioned Chappell, Cranton, Magaziner, and Miranda, to the Liaison Committee to the ACAM.[4]

The 2001 protocol also names, as a "prominent expert," current ACAM president-elect Jeanne Drisko, Clinical Assistant Professor of Alternative Medicine at the University of Kansas Medical Center, Kansas City, Kansas, and Research Consultant at the Center for the Improvement of Human Functioning International in Wichita, Kansas.[185] Among the methods that the latter Center's Web site espouses are hair analysis; chelation; intravenous vitamin C; "orthomolecular medicine"; "colon health"; and, ironically, the toxic heavy metal colloidal silver, which it calls "completely nontoxic.[186]" The Center has a restaurant at which patients, whom it calls "co-learners," can eat lunch while listening to a lecture entitled "Improving AUTISM Outcomes with Mercury Chelation." It sells "supplements," books, audiotapes, videotapes, software, and "health accessories."

The Center charges "co-learners" $600 for an initial consultation and "$2000 or more" for initial laboratory tests.[187] Payments must be made in advance; the Center does not extend credit or accept third-party payments. Fees are usually not covered by insurance "because many of the services provided by The Center involve biochemical and nutritional concepts unfamiliar to insurance companies and standard medical people....[187]" A Sample Report page, which gives the results of a "Health Hunter/Beat The Odds Mega (Comprehensive) Panel," reveals what some of those unfamiliar concepts are: claims for "nutrients" and antioxidants that are exaggerated, misleading, or simply false, but that will likely entice co-learners to spend money at the Center's "Gift of Health" store.[188]

Dr. Drisko was a signatory of the Discovery Institute's pro-Intelligent Design "Dissent from Darwinism" petition.[189] She is also a TACT co-investigator.[7]

Another "prominent expert" on the TACT Liaison Committee is psychiatrist Michael Schachter, the ACAM president from 1989 to 1991. During the 1970s, Schachter had been investigated by the New York State Board of Professional Conduct for allegedly treating cancer patients with Laetrile and "a secret formula called MA-7.[190]" He recommended Laetrile (amygdalin) on his Web site as recently as February 2003, and continues to report "success stories" in which he has given it to cancer patients, "although some of these patients have since passed away.[191,192]" His current recommendations for cancer include coffee enemas, chelation, shark cartilage, bovine tracheal cartilage, and IV hydrogen peroxide.[193] In 2003 he recycled the original decalcification claim for chelation for CAD, but associated it with a new treatment:


The amount of Calcified Plaque in your Coronary Arteries is directly related to your risk of having a heart attack. Cardiovascular decalcification can decrease your risk of having a heart attack. New research studies have shown that coronary artery plaque calcification is caused by an infection that can be treated.

If you have Heart Disease, Coronary Artery Disease, Angina or have had Bypass or Stents you are probably a candidate for NanobacTX and this Study.

Compared to surgery or other treatment, NanobacTX is extremely inexpensive at $290 for a one-month prescription. Patients are expected to pay for their medication as a part of participation in this program. At this time, you should assume that your insurance company would not cover NanobacTX.

CALL our office today to see if you qualify to participate & receive NanobacTX.[194]



Dr. Schachter is also a TACT co-investigator.[7,38]

Study Design
The NCCAM press release in 2002 announced that the TACT was to involve over 2300 subjects -- each more than 50 years old and having had an MI -- at "approximately 100 research sites across the country...[that] will represent a mix of clinical settings--university or teaching hospitals, clinical practices or cardiology research centers, or chelation practices.[2]" That number of subjects was higher than the 1600 stated in the original proposal.[4] More recently, the number appears to have been reduced to 2000,[49] possibly because of difficulty in recruiting subjects. The 2003 TACT protocol had predicted that 36 months would be adequate to recruit 2372 subjects.[5] After 36 months, however, only 1000 subjects had been recruited.[37] In 2007, twenty-one new sites in Canada, most appearing to be chelation practices, were added.[7,38,48195]

Each trial site must have a "senior investigator," and each senior investigator "must have substantial experience in the treatment and management of CAD and in the design, implementation and evaluation of clinical trials.[1,5]"

According to the TACT protocols there are 4 arms in the study, reflecting the practice of chelationists to give "high-dose antioxidant vitamin and mineral supplements" along with EDTA. There are 2 chelation arms whose subjects each receive 40 infusions of the chelation solution, with a low-dose oral vitamin and mineral regimen and either a high-dose oral vitamin and mineral regimen ( Table 1 ) or placebo pills, and 2 nonchelation arms whose subjects each receive 40 placebo infusions of 563 mL normal saline and 1.2% dextrose, with the low-dose oral regimen and either the high-dose regimen or placebo. The ingredients of the chelation infusion include[5]:

500 mL sterile water;
"Up to" 3 g Na++EDTA (adjusted for creatinine clearance);
2 g MgCl;
100 mg procaine HCL;
2500 u heparin;
7 g ascorbate;
2 mEq KCL;
840 mg NaHCO3;
250 mg pantothenic acid;
100 mg thiamine; and
100 mg pyridoxine.
 


The high-dose oral regimen (or placebo) is to be taken twice daily.[5]

Each subject is to receive 30 weekly infusions followed by 10 "maintenance" infusions given less frequently. Each infusion is to be administered "over 3 hours at a...rate of 166cc/hr.[5]" "Every effort will be made to conduct infusions with the smallest gauge catheter or a 25 gauge butterfly needle as this will limit the maximum infusion rate.[5]" "The entire regimen can take up to 27.5 months to complete.[4]" There is a requirement that each clinical site have "intravenous calcium gluconate available and be trained in recognizing and treating hypocalcemia.[5]" There are no requirements, in the protocols that were provided to us, for continuous electrocardiographic (ECG) monitoring, IV infusion pumps, the continuous presence of nurses or physicians, materials for administering advanced cardiac life support, or the presence of individuals trained in advanced cardiac life support protocols.

The 2001 protocol describes the ingredients of the low- and high-dose supplement regimens "defined by consensus with the ACAM Liaison Committee.[4]" The NIH "redacted" the ingredients of the oral supplement regimens from our copy of the 2003 protocol, stating instead, "p 38 withheld in entirety 'proprietary info' [sic].[5]" We question why such ingredients, none proprietary by itself and all given in the context of a taxpayer-sponsored trial, should be "proprietary." If the reason is that the mixtures might eventually be marketed for the treatment of CAD, then this should have been disclosed on the consent form, and the mixtures would have required Investigational New Drug exemptions.[196]

Blinding?
The experimental solutions must be mixed on-site. The 2003 TACT protocol describes a method to preserve blinding and reports that this "has been piloted successfully," presumably in a supervised, academic setting.[5] Nevertheless, the mixing procedure presents simple opportunities for distinguishing between the chelation and placebo solutions. For example, the site coordinator must inject 14 mL of concentrated ascorbate or sham solution into a 500-mL IV bag. The plan calls for the 14-mL solutions to have similar viscosity and to appear similar in color, but a tiny drop applied to the tongue during transfer would instantly identify the ascorbate by its sour taste. Ascorbate goes exclusively with the Na2EDTA solution.

"Oxidative Stress" Markers Scrapped
The TACT RFA and the original TACT protocol included plans for a substudy of biochemical markers of oxidative stress.[1,4] The 2003 protocol lacks the substudy, without commenting on its absence. Perhaps the explanation is that it is not yet clear what markers are clinically useful for measuring oxidative stress, and what subjects are at particular risk. In 2002, more than a year before the first subjects were recruited for the TACT, 2 NHLBI-supported scientists made the point after noting that human trials of antioxidants for atherosclerosis had been disappointing:


With the benefit of hindsight, the decision of the 1991 National Heart, Lung, and Blood Institute workshop to give a green light to trials, even trials that use safe, naturally occurring antioxidants, may have been premature. Not knowing how LDL is oxidized in vivo, we cannot be certain which antioxidants are likely to be most effective. We lack markers that would let us evaluate the efficacy of any given antioxidant intervention, and we lack criteria for rational selection of patients under high oxidative stress. Until we have such basic information, we should put a hold on further clinical trials. Instead, we should concentrate on developing the scientific base that will enable us to design an appropriate trial to test the oxidation hypothesis.[151]



That opinion is consistent with the NCCAM's own 2002 statement of "2003 Research Priorities," mentioned above: "...the research portfolio would be better served by an increased emphasis on studies of the mechanisms underlying CAM approaches....[179]" We observe that Na2EDTA is not even a safe, naturally occurring antioxidant. This is another reason that if science had been the real issue, the NIH ought to have "put a hold" on the TACT.

Duration of Follow-up: Endpoints
Depending on when they have been recruited, subjects will apparently be followed for as little as 1.5 years or as long as 5 years.[5] The end of the follow-up period is stipulated as the "study close-out" date. Because the "expected completion" is now predicted to be July 2009, we wonder whether follow-up periods will be longer than 5 years for some subjects.[38]

The 2001 TACT protocol stipulated a 5-part, composite primary endpoint comprising all-cause mortality, MI, stroke, hospitalization for angina, and hospitalization for congestive heart failure. It included at least 14 secondary endpoints, including the individual components of the primary endpoint.[4] The 2003 protocol retains most of the composite primary endpoint, but replaces "hospitalization for congestive heart failure" with "coronary revascularization." It also calls for examining the individual components of the primary endpoint, but warns that "the trial will not have adequate statistical power to test any individual component of the primary endpoint.[5]" The 2003 protocol stipulates several subgroup comparisons and "economic analyses, cost-effectiveness analyses, and quality of life data collection and analyses.[5]"

Chelationists as Co-Investigators
After the announcement of the TACT, the ACAM issued a press release announcing that its "member physicians will be part of a nationwide effort to recruit a patient study population" for the trial.[197] ACAM President Ron Hoffman, another prominent expert TACT appointee, said that he "look[ed] forward to chelation taking its rightful place among officially acknowledged cardiac treatment strategies.[197]" As of September 2007, nearly 100 chelationists had been designated TACT co-investigators.[7] For unstated reasons, 20 that had previously been listed on ClinicalTrials.gov were now absent from the NCCAM roster.[7,117,198] Neither the 2001 nor the 2003 protocol describes a complete set of criteria that would qualify a potential site investigator to be included in the TACT.[4,5]

In our opinion, the activities and associations of chelation practice co-investigators should have disqualified almost all of them. Contrary to language in the 2001 TACT protocol, few if any "have substantial experience in the treatment and management of CAD and in the design, implementation, and evaluation of clinical trials.[4]" Rather, most have denigrated proven treatments for CAD and other serious diseases, instead offering "genuine practice builders,[199]" such as chelation, NanobacTX, Laetrile, antineoplastons, IV hydrogen peroxide, detoxification, "longevity medicine," "energy medicine," shark cartilage, "immune boosters," homeopathy, "magnetic healing," "antiyeast medicine," "Wilson's thyroid syndrome," "colon hydrotherapy," and more.[7] At least 18 have been subjected to state medical board actions, criminal convictions, or federal civil judgments[200,201] At least 3 are convicted felons.[60,61,202,203]

Few, if any, have been involved in legitimate clinical trials. Instead they have either reported or accepted the claims of dubious "case series" of chelation, discussed in Part III of this article. Most are members of organizations that have advocated "officially sanctioned research" as a ruse to shield "alternative medicine" practices from regulatory scrutiny.[130-132, 140-142, 204] More than 20 are officers in those organizations.[204] At least 7-- Ali, T. Born, Carter, Casdorph, Chappell, Miranda, and Rozema -- were members of either the GLACM IRB that the FDA cited for numerous violations of human studies protections, or of the closely related ACAM IRB.[7,55,140,144,145,204] Co-Investigator Richard Fleming, who may not even be a chelationist, is currently under federal indictment for allegedly sending fabricated data to the sponsor of a clinical trial.[7,205]

A TACT co-investigator in British Columbia, Galina Bogatch, appears to be licensed in Canada only as a naturopath.[206] Total Sensory Wellness Center in Waldorf, Maryland, is owned by a naturopath and appears to have no medical or osteopathic doctors among its practitioners.[207] The Web site of the Coyote Healing Center, a TACT chelation site in Tucson, Arizona, identifies David Rupley is its sole "doctor.[208]" Rupley is not licensed by the Arizona Medical Board; he is licensed by the Arizona Board of Homeopathic Medical Examiners, which appears to be a regulatory haven for dubious practitioners.[208-210] The FDA Bioresearch Monitoring Information System (BMIS) identifies the Investigator at "Coyote Healing Ctr" in Tucson as Lewis Mehl Medrona (sic; the correct spelling is "Mehl-Madrona"), and the Submission Date as April 13, 2005.[7,211] Mehl-Madrona's curriculum vitae, however, mentions neither the TACT nor the Coyote Healing Center, and reveals that he has lived in Saskatchewan, Canada, since 2005.[212] The NIH and pertinent IRBs ought to know that neither naturopaths nor homeopaths are competent "in the treatment and management of CAD," and they must know that Mehl-Madrona cannot act as the PI for a study site in Arizona if he lives in Canada.

The FDA BMIS posts records of trial sites and their corresponding investigators.[211] Such records, which are updated quarterly, demonstrate that a trial's sponsor has submitted required information about sites and investigators to the FDA.[213] As of September 3, 2007, the BMIS had no record of the Total Sensory Wellness Center -- listed on ClinicalTrials.gov as a TACT site since June 2004 -- or of 21 other US TACT sites.[7,211,214]

At least 3 TACT co-investigators are officers in the North Carolina Integrative Medical Society (NCIMS), which has positioned itself squarely in opposition to standards of medical care promulgated by the North Carolina Medical Board.[215] The Board has recently charged one of them, Rashid Buttar, with selling "unproven and wholly ineffective" treatments, including IV EDTA and hydrogen peroxide, to cancer patients:


Dr. Buttar charged exorbitant fees for his ineffectual therapies. The total cost of the intravenous injections and other therapies for these cancer patients at times ranged in the thousands, sometimes tens of thousands, of dollars. Not only would Dr. Buttar order and have administered unproven and ineffectual therapies for Patients A, B and C in an attempt to drive up his billings, he would also order numerous tests and lab work for these patients that had no rational, medical relationship to the Patients' cancer diagnosis. Moreover, many tests and lab work that were ordered by Dr. Buttar were never adequately justified in the medical records of the patients, were never linked to the patients' diagnoses or clinical condition, and in some instances never interpreted.[216]



Dr. Buttar is President of the NCIMS and the current chairman of the ABCMT.[217,218] It is instructive to compare the North Carolina Medical Board's statement with a recent description of Dr. Buttar by Congressman Burton and Congresswoman Diane Watson [D-CA].[219]

As previously stated, about 70 of 80 identifiable TACT chelation practice Web sites promote chelation.[7] Some reproduce, verbatim, several of the statements that the FTC cited as false in its complaint against the ACAM in 1998.[163,220,221] 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.[222]

Such postings introduce bias into the trial and are contrary to Federal Regulations that prohibit investigators from promoting investigational new drugs[223]; the postings may also constitute "misbranding" of Na2EDTA, for which there is a precedent involving "chelation pioneer" H. Ray Evers.[18] 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....[1]" 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.[225]



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?

Almost all chelationist co-investigators are members of an organization or one of its offspring founded "to promote the use of EDTA chelation therapy for cardiovascular disease.[34]" The ACAM has repeatedly misrepresented the evidence for safety and effectiveness of chelation.[30,33,34,152,164,204] The future success of the ACAM and its related organizations is substantially dependent on the outcome of the TACT, which it expects to vindicate its claims.[41,100,102,197] Thus it is imprudent for the NIH to rely on ACAM members to answer subjects' "questions about the risks[6]"; to recognize, treat, and report adverse events; to maintain allocation concealment and blinding; or to provide the objective and thorough reporting of data necessary to minimize bias in a trial.

Many TACT sites have been approved by the Sterling IRB.[117,226,227] The Sterling IRB's 2003 Investigator/Site Questionnaire asked whether any sub-investigator or member of the research staff had been convicted of a crime, had been subjected to a medical license action, had received a warning letter from the FDA, and other questions pertinent to the protection of human subjects and to the ethical conduct of research. Several TACT co-investigators should have answered "yes" to those questions.[141,200,201,204] Did they? If so, how did the IRB determine that they were acceptable co-investigators?

Will Subjects Receive Indicated Medical and Surgical Therapies?
The 2003 TACT protocol states:


All surgical and medical therapies will be at the discretion of the responsible health care providers. Nonetheless, procedures will be implemented to comply with the TACT protocol and to ensure that participants are afforded the same quality of care that is given in other NIH funded trials.[5]



Despite that assurance, surgery and cardiologic procedures will remain entirely "at the discretion of the health care provider." Medical therapies, however, are to be monitored quarterly by the Data Coordinating Center, which will give a "quarterly 'Report Card'" to each site. If a site is not in compliance with established guidelines for post-MI patients, it will be queried to "determine [the] reasons...Sites with continued non-compliance [and] no valid reasons for such will be discussed in the Steering Committee. Possible actions range from enhanced educational efforts to suspension from future patient accrual. In all cases they will be obligated to continue infusing and following randomized patients.[5]"

Such language seems surprising for an NIH-sponsored protocol. It is reasonable to expect the NIH to involve only co-investigators who practice according to current ethical and clinical standards, as required by universally accepted human studies treatises. Chelationists, however, routinely eschew proven medical and surgical treatments for coronary disease, instead offering questionable "alternatives.[7, 228-230]" TACT Chelation Consultant Martin Dayton has written:


Chelation is often used as a safer method to replace much costlier conventional surgical and related medical procedures.[57]

Unlike surgical approaches, no strokes, deaths nor heart attacks have been reported to be due to intravenous chelation therapy, and fewer side effects are reported than with many pharmaceutical medical treatments.[57]



Dr. Dayton's practice Web site includes a consent form with this language:


I am informed that I may benefit and/or be harmed by having, refusing, quitting or delaying either customary standard medical care and/or non customary non standard medical care.

I hereby release my physician, Dr. Dayton, and facility in which I am being diagnosed and treated from liability from my CAM care[sic].[231]



The ICIM (formerly the GLCCM), whose president is "prominent expert" L. Terry Chappell and many of whose members are TACT investigators,[204] recently announced a:


...Congestive Heart Failure Task Force which offers all ICIM members the opportunity to participate in a patient-based outcome study to investigate and validate beneficial therapeutic nutritional alternatives to orthodox drug-based protocols. The task force is intended to be a collaborative effort among physicians who have experienced success replacing conventional treatment models and physicians who are seeking to treat patients they may have otherwise felt compelled to refer to orthodox practitioners...Several of the participating Task Force members have already treated difficult cases with cutting-edge therapies not yet in general use which will offer ICIM members advanced information. This promises to be a genuine practice-builder.[199]



Some chelationists object to standard therapies not only for clinical practice, but for trials in particular. "Prominent expert" Elmer Cranton offered this in his repudiation of the negative findings of the Canadian PATCH trial[27,28]:


[Many subjects] were given potent anti-anginal drugs...There was...no true "placebo" group. The F.D.A. in the United States has never approved a new drug to treat angina without first requiring trials wherein all other anti-anginal medications had been discontinued.[161]



Thus, chelation site co-investigators have a choice: They may either uphold the current standards of care for patients with coronary disease, and thus be armed from the outset with what they consider to be an ironclad objection to the study, or they may withhold standard therapies, thus putting TACT subjects at undue risk.

Comments on the TACT Consent Form
The TACT consent form (version June 16, 2003) was provided to us, with some parts "redacted," under the FOIA.[6] It states, "(EDTA) is approved for use by the FDA as a treatment for lead poisoning but not for coronary artery disease." In fact, the FDA has not approved disodium EDTA, the preparation used in the TACT, for the treatment of lead poisoning.[12] That approval goes to calcium-sodium EDTA, which does not carry the risks for acute hypocalcemia or bone loss, although it does carry a significant risk for renal toxicity.[31] The FDA, moreover, has done more than merely not approve disodium EDTA for CAD: It has specifically contraindicated the drug for the treatment of "arteriosclerosis.[12]"

The consent form also fails to state that the standard protocol for treating lead poisoning with CaEDTA involves different dosing and timing, and careful monitoring in a hospital setting -- unlike the way chelationists administer Na2EDTA. Those pieces of information, the reasons for them, and the implications with regard to the character of chelation practice co-investigators are things that IRBs and prospective subjects have a right to know. Instead, the form blandly states that "chelation therapy has been practiced in the community for many years" and is "thought to bind specific toxic elements circulating in your blood.[6]" It also states, "if you are assigned to the chelation group you will receive a standard intravenous mixture established by the American College for Advancement in Medicine.[6]" Such statements amount to tacit endorsements of the practice and the practitioners.

The consent form fails to state that chelation offered for CAD has long been considered fraudulent by the FDA, the FTC, medical scholars, and respected professional organizations.[9-11, 18, 63,65,78, 124-129] It fails to state that a plausible scientific rationale for the treatment is lacking.[147,148] 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.[21-28] 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.[176-180]

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]

The consent form fails to cite several realistic risks. Among these are bone loss, of particular concern in a study group that includes postmenopausal women, and the paradoxical generation of oxygen-free radicals.[23,148]

The consent form fails to state that the ACAM is not the authoritative, ethical organization that its name implies, but has consistently made unsupported claims for chelation and has been cited for this by the FTC.[30,33,34,152,163,164] It fails to state that the ACAM, the GLACM, and many of their members, including several TACT co-investigators, have systematically endangered patients under the guise of human studies, and several have been cited for this by the FDA.[7, 130-132, 140-142, 204] It fails to state that many key ACAM members, including several TACT co-investigators, have been disciplined by medical boards, convicted of crimes, or indicted for either civil or criminal actions.[17,18,20,59-62, 200,201] It fails to state that there have been 20-30 deaths associated with Na2EDTA infused by ACAM members.[13-20]

The form fails to state that every site investigator who has previously treated patients with disodium EDTA for atherosclerosis, outside of the context of a legitimate study, has not given it merely "off-label," but in direct contradiction to its label.[12] It fails to state that merely 20 years ago such a practice was reasonably described as "an abuse of the physician's freedom of choice,[11]" and subsequent unfavorable findings in controlled trials have reinforced that description. It fails to state that most TACT chelation site co-investigators promote numerous other dubious practices and, contrary to human studies ethics, scientific integrity and federal law continue to promote chelation as safe and effective for CAD even as the study purported to make this determination is under way.[7]

The form fails to state that the "standard intravenous mixture established by the ACAM" is not based on rigorous, ACAM-sponsored research, but is merely a reiteration of language in the edetate (Endrate) package insert coupled with a fanciful batch of supplements.[12,33] The form lacks language explaining redacted "proprietary info" that would seem to describe the oral supplement mixtures used in the TACT.[6,233] The disclosure of proprietary interests is pertinent to informed consent.

The consent form fails to state that ACAM members typically discourage standard therapies for CAD. Instead, the form places the burden of such therapeutic decisions on the subjects themselves: "You should continue to use proven standard medicines for heart attack patients whether or not you participate in this study.[6]"

Could the TACT Lead to Significant Changes in Practice?
The realities of chelation "as practiced in the CAM community[5]" predict that even an entirely negative outcome would not dampen the enthusiasm of advocates. Most now claim that chelation's primary purpose is to remove toxic heavy metals, which secondarily "reverses or slow[s] diseases of aging," CAD being merely one among more than 70.[13,47,57, 101-105, 114,115,119] In the same year that Dr. Lamas assured American Heart Journal readers that a large trial of chelation for CAD would "lead to changes in clinical practice,[29]" his colleague Martin Dayton summarized the opinions of chelationists for an article about "detoxification therapies" in InnerSelf Magazine:


Martin Dayton, M.D., of Florida, who is board-certified in family medicine, chelation therapy, and clinical nutrition, says that chelation therapy has multiple benefits, and long life is one of them: "Dramatic increases in life span are found with chelation. While there are no longevity studies per se, this conclusion is implied indirectly by studies which show a lessening of killer degenerative diseases. In fact, chelation favorably impacts all four major causes of death in the United States [heart disease, cancer, cerebrovascular disease, and lung disease]."

Once in the bloodstream, EDTA attaches itself to heavy metals such as lead, cadmium, and mercury and holds onto those toxic substances until they exit the body through the urine. Dr. Dayton explains why removal of these substances is vital to good health: "The toxic material prevents normal function and repair. For example, lead prevents normal enzymatic processes so that the body cannot function properly and repair itself. This leads to premature aging and the premature development of disease. Removal of toxic material through chelation keeps the body functioning optimally."

Dr. Dayton notes that an excess even of iron, which is necessary for life, accelerates free radical production and causes harm... "At this time, arterial clogging accelerates. Chelation removes this excess iron."

Since modern people are overwhelmed by pollutants, Dr. Dayton recommends chelation therapy for anyone over thirty. "Lead is found everywhere, in the air we breathe, the water we drink, the food supply. It is even found at the North Pole. Lead and other toxic pollutants are hard to avoid in today's world..."

"Unclogging carotid blockage is vitally important because the American College of Physicians states that patients with an obstruction of 70 percent of greater are at a high risk for stroke. They even recommend chelation therapy as a preferred treatment. I take that to heart and use chelation therapy on these individuals. People who have carotid artery disease improve as their arteries open up. I see this happen over and over again.[234]" (brackets in the original)




According to Dr. Dayton, who in 1986 had been convicted of mail fraud,[61] he and Dr. Lamas began planning a chelation trial well before the "TACT was designed and funded.[57]" This is consistent with Dr. Lamas' statement that his collaboration with chelationists began in "early 1999.[4]" It is surprising that more than a year later Dr. Lamas could have remained naive enough to predict that a negative CAD trial would significantly reduce chelation advocacy.

In researching the literature for his rebuttal to Ernst's 2000 editorial, moreover, Lamas ought to have discovered that "prominent experts in chelation therapy" had repudiated every negative trial of chelation for atherosclerosis, and he might have correctly predicted that they would continue to do so.[152-162] Even at that time, the Canadian PATCH trial was anticipating the TACT by involving ACAM members in an attempt