Medscape J Med. 2008; 10(5): 115.
Published online 2008 May 13.
Medscape J Med. 2008; 10(5): 115.
Published online 2008 May 13.
Why the NIH Trial to Assess Chelation Therapy (TACT) 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.
For the rest of the detailed report:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438277/
