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The Trial to Assess Chelation Therapy: Equivocal as Predicted

The ill-advised, NIH-sponsored Trial to Assess Chelation Therapy (TACT) is finally over. 839 human subjects were randomized to receive Na2EDTA infusions; 869 were randomized to receive placebo infusions. The results were announced at this weekend’s American Heart Association meeting in Los Angeles. In summary, the TACT authors report a slight advantage for chelation over placebo in the “primary composite endpoint,” a combination of five separate outcomes: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina:

 

Although that result may seem intriguing, it becomes less so when the data are examined more carefully. First, it barely achieved the pre-ordained level of statistical significance, which was P=.036. Second, none of the individual components of the composite endpoint achieved statistical significance, and most of the absolute difference was in coronary revascularization–which is puzzling:

Third, the difference in the primary composite endpoint was limited to diabetic subjects (about 30% in each group), as shown here:

 

Since the numbers of diabetics were substantially smaller than the total, and since, as the authors themselves admitted, “subgroup analyses can be unreliable,” this finding may or may not reflect a real phenomenon. There was also a fair amount of incomplete data, as shown here:

 

Unfortunately, the authors did not report the numbers of dropouts from each of the arms of the study. If there was a substantial discrepancy, that alone could explain an apparent difference in outcome.

The authors reported that the treatment was safe:

 

We are not told how many of the 79 who discontinued infusions came from each arm, however. Regarding the two deaths that were “possibly or definitely related to study therapy,” could those have been the same two subjects discussed here? It seems unlikely, because in each of those cases “The site investigator has assessed the causal relationship between the study drug and the serious adverse event as not associated stating the cardiopulmonary arrest was due to progression of the disease under study,” and the SAE reports from Duke University barely challenged those assessments. That makes me wonder about the details of the remaining 180 reported deaths, even though they were nearly evenly distributed between the active and placebo groups.

 The authors offered these caveats and conclusions:

 

I agree with the caveats and with the final conclusion. I do not agree that “additional research will be needed.” Now, for the “I told you so” part of this post.

Not Definitive, Somewhat Informative

When Gervasio Lamas, the Principle Investigator of the TACT, announced his plans to pursue a trial of chelation, he touted it as

a definitive trial [that] would, once and for all, either put to rest the lingering questions of efficacy or add EDTA chelation to the armamentarium for clinicians who treat patients with coronary disease.

When the TACT began in 2002, NCCAM Director Stephen Straus opined:

The public health imperative to undertake a definitive study of chelation therapy is clear. The widespread use of chelation therapy in lieu of established therapies, the lack of adequate prior research to verify its safety and effectiveness, and the overall impact of coronary artery disease convinced NIH that the time is right to launch this rigorous study.

The description of the TACT on ClinicalTrials.gov promised this:

The results of TACT will provide either a significant positive result or an informative null result upon which rational clinical decision-making and health policy can be based.

Clearly the $30 million TACT, the most expensive “CAM” trial yet paid for by taxpayers, has not put to rest lingering questions of efficacy, although those did not really exist prior to its inception. Rather, the trial’s results are consistent with this prediction:

The Likely Outcome

Even if the TACT is completed, which it should not be, it is unlikely to reduce the promotion of reckless uses of Na2EDTA. Whatever the outcome, chelationists have already positioned themselves to continue the practice: By virtue of ridding the body of toxic heavy metals, they claim, chelation is useful for more than 70 conditions. Without exception, chelationists have refused to accept previous results that contradict their beliefs. Their response to the TACT, should it yield definitive, negative results, is unlikely to be different.

The trial, moreover, is unlikely to yield “an informative negative result” even though chelation is almost certainly ineffective for CAD. It is more likely to yield ambiguous results. There are multiple endpoints, including subjective quality-of-life measures, and several subgroup analyses. The variety of trial settings increases the likelihood of heterogeneity of procedures and reporting. Promotions of chelation by TACT co-investigators have already introduced unacceptable bias into the trial. There is ample, additional opportunity for mischief, and ample reason to think that several co-investigators are inclined to make it. The statistical analyses will not be Bayesian.

Thus, merely on the basis of chance and bias, it is likely that some outcome data in some subgroups will differ sufficiently, between those receiving Na2EDTA and those receiving placebo, to reassure chelationists that chelation “works” and to sustain “lingering questions of efficacy” in the minds of apologists. Dr. Lamas himself has made much of 2 or 3 “tantalizing positive secondary outcomes” of a previous trial in which only 15 subjects received Na2EDTA, and in which the remaining 30 secondary outcomes and all 7 primary outcomes were unequivocally negative. The all-but-inevitable “tantalizing positive secondary outcomes” of the TACT would likely lead to years of additional, unnecessary trials or, at the very least, unremitting peddling of chelation by practitioners armed with fresh fodder in their perpetual battle against rational standards of care.

The ACAM, the PPO that most pushes chelation, is already licking its chops to have Dr. Lamas present his own tantalizing positive secondary outcomes at their fall meeting in Las Vegas. It’s a cinch that whatever else comes of the TACT, it will protect quacks from state medical boards for years to come.

It’s ironic, then, that the TACT results are informative in an important way that its authors seem to have overlooked: it convincingly demonstrates that the claims of chelationists have been bogus all along. That’s because those claims have been far more dramatic than even the small effect that the TACT may appear to support. Typically, chelationists, including those involved in the TACT, claim “improvement” or even “marked improvement” in 80-90% of patients with ischemic heart disease or other vascular disease. A review of such claims is here.

Note to Medical Journals: Publishing the Formal TACT Report would Violate your own Ethics

The TACT was an unethical trial for numerous reasons. What follows are a couple of those reasons that are not in dispute, quoted from this summary:

  • We have shown, and both the federal Office of Human Research Protections (OHRP) and the University of Miami IRB have acknowledged, that the TACT proceeded with a misleading consent form—so misleading that any change now, more than 6 years after the trial began, couldn’t possibly reverse the damage already done. Misleading statements in the consent form included a strong implication that the study drug was the relatively less dangerous calcium-sodium ETDA, not the very dangerous disodium EDTA used in the trial. The consent form also failed to state important risks, including death.
  • We also showed, and the OHRP and U. Miami IRB also agreed, that many of the investigators in the TACT have criminal records, histories of discipline by state medical boards, histories of membership in IRBs disciplined by the FDA, and other indications of incompetent practices or worse.

Most medical journals subscribe to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, established by the International Committee of Medical Journal Editors. The Uniform Requirements include honoring the Helsinki Declaration, which includes these passages:

24. In medical research involving competent human subjects, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, and any other relevant aspects of the study.

16. Medical research involving human subjects must be conducted only by individuals with the appropriate scientific training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional. The responsibility for the protection of research subjects must always rest with the physician or other health care professional and never the research subjects, even though they have given consent.

30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research…Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

So don’t do it.

Posted in: Clinical Trials, Health Fraud, Medical Ethics, Politics and Regulation, Science and Medicine

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