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

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.[1,2,3,4,5,6] 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.[9,10,11]"

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.[13,14,15,16,17,18,19,20]

Prior to the TACT, 4 RCTs and several substudies of chelation for either CAD or PVD, involving 285 subjects, had been reported.[21,22,23,24,25,26,27,28] 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.[1,2,3,5,6,30] 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.[33,34,35] 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[7,9,10,11];

  • 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]

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