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

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

Disclosures

Medscape J Med. 2008;10(5):115 

In This Article

II. The Genesis of the TACT

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]

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.[176,177,178]

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]"

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]

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]

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.

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.

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]"

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.[130,131,132,140,141,142,204] 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.[208,209,210] 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?

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.[7,228,229,230]" 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.

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.[9,10,11,18,63,65,78,124,125,126,127,128,129] 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.[21,22,23,24,25,26,27,28] 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.[176,177,178,179,180]

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.[7,130,131,132,140,141,142,204] 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.[17,18,20,59,60,61,62,200,201] It fails to state that there have been 20-30 deaths associated with Na2EDTA infused by ACAM members.[13,14,15,16,17,18,19,20]

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]"

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.[13,47,57,101,102,103,104,105,114,115,119] 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.[152,153,154,155,156,157,158,159,160,161,162] Even at that time, the Canadian PATCH trial was anticipating the TACT by involving ACAM members in an attempt to deflect their predictable objections.[27,235] After the PATCH published its negative findings in 2002, it became clear that the attempt had been futile.[161,235] Thus, another trial that finds no evidence that chelation is effective for CAD, particularly one in which all subjects are expected to receive standard therapies, is unlikely to be the first to persuade true believers to change their minds.

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