Nov 05 2012
The result of the Trial to Assess Chelation Therapy (TACT): As underwhelming as expected
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29 Responses to “The result of the Trial to Assess Chelation Therapy (TACT): As underwhelming as expected”
Ewww.
The study has very many serious problems, but I wouldn’t critcize a group for analyzing a primary endpoint if it was prespecified, cause you’ll get splinters under your fingernails. Note: I haven’t studied how they allocated their alpha (chance of false positive conclusions) among hypotheses to be tested. That needs prespecification too.
I’m wondering,
1. Why the vitamins? Why test chelation plus vitamins rather than just testing chelation? Do they think vitamins are necessary for the chelation to work?
2. Why the heparin? Could it conceivably have a therapeutic effect?
3. How can you keep from shouting “we told you so”?
4. Why doesn’t the media pick up the story of TACT criticism?
“Why doesn’t the media pick up the story of TACT criticism?”
They are but not as much as one would hope. Dr. Gorski linked to an AP story in the previous entry. Here it is again in another paper:
http://www.thenewstribune.com/2012/11/04/2355547_doctors-debate-value-of-fringe.html
From the New York Times story:
“And some skeptics were not persuaded at all. Dr. Steven Nissen, head of cardiovascular medicine at the Cleveland Clinic, said the study was “fatally flawed,” with many of the doctors involved being on the fringes of medicine and many patients dropping out of the trial. He said if people got the mistaken idea from the study that chelation was beneficial “it would be a public health catastrophe.” ”
Sounds like Dr. Nissen is on the same page with Drs. Gorski and Atwood.
http://www.nytimes.com/2012/11/05/health/chelation-therapy-shows-slight-benefit-in-heart-disease-clinical-trial.html?_r=0
“Moreover, 17% withdrew consent,”
I wonder if someone more familiar than I with RCTs could comment on the typical fraction of participants who withdraw consent and for what reasons consent is typically withdrawn? I can understand drop outs. Withdrawal of consent seems a bright red flag that something isn’t right.
I saw this news elsewhere, and I noticed that it included a blood thinner (heparin) only in the treatment group. I’m no doctor, but aren’t blood thinners already a known way to reduce heart disease? Is there a special reason to combine a blood thinner with chelation (like to counteract some side effect), or is this just a trick to mix real treatment with fake treatment to drag up the average?
You know, I should probably have thought a bit more about the heparin in the mixture. I can’t think of any reason to include it, unless the whole mixture being given was somehow thrombogenic. (Maybe Kimball, who has been following TACT since a couple of years before I ever started blogging, might have more insight.) In any case, it’s very clear that the placebo was not a good placebo, given that it lacks procaine and the heparin, while also contains 1.2% dextrose that the chelation mixture doesn’t contain. Indeed, some are speculating that the dextrose in the placebo could potentially have been harmful to the diabetics, thus making an apparent difference not because chelation does any better in diabetics but because diabetics were being hurt by the placebo. I’m not so sure that a weekly dose of heparin would be likely to help that much, given that heparin is out of the system in just a few hours, but I suppose it’s possible. One thing it can do for sure is to increase the risk of bleeding complications.
Another thought occurred to me. Chelationists will obscure it by pointing to the diabetes subgroup, but this study is absolute, stone-cold evidence that chelation therapy does not work in patients with cardiovascular disease but without diabetes. In that group, not only was there no difference in the aggregate primary outcome (all events), but there appears to have been no difference in any of the individual prespecified outcomes. For non-diabetics with heart disease, this is as completely negative a trial as one can imagine. For diabetics, it’s almost certainly at best equivocal, with a result that can likely be explained by something other than a therapeutic effect due to the chelation therapy.
@Dr. Hall, I completely agree about the micronutrient side of the study. The vitamins and minerals selected, as well as the doses, make zero sense when looked at independently or even as an aggregate.
Indeed, according to the text: “The dosing and components of the high-dose oral vitamins were developed with the collaboration of ACAM and represent the typical multi-intervention treatment offered by chelation
therapy practitioners.”
Which is another way of saying the developers were completely whacked out and had zero grasp of nutrient requirements or function, as any real nutrition professional would point out to the PIs (and probably did). The selections certainly have zero rhyme or reason relative to CVD outcomes. For example, why give 500% of the Vit A reqt but only 25% of the vit D reqt – this is a great way to exacerbate VD def or create a functional VD deficiency. (The two complete for the same DNA sites at pharmacologic intakes).
If I am reading this right, aren’t the patients in the Chelation + Megadose arm getting even higher intakes? That would be 8.2g VC (!), 6500% of B5 (!!), and 7500% of B6. How did this get through Human Subjects? I think their rationale was based on what they could get approval for on the ULs – it certainly isn’t based on science.
Upon reflection, this will make a great study for my nutrition grad students to critique (read “demolish”) next semester, so thanks for the head’s up!
What we have here so far is a presentation at a meeting and an abstract. Yes?
I wonder about the process of getting this study into the peer-reviewed literature. What journal will accept it? Will the reviewers require the authors to demonstrate security of blinding? Will the reviewers get the authors adequately to defend the lack of comparability between placebo and test treatments?
It doesn’t look likely that either of those questions is answerable to a high enough standard for any respectable journal and the manuscript should be rejected outright.
The other major point, to which both Drs. Gorski and Attwood have alluded, is that even if the positive outcome in part of this study is real, the plain fact that it takes a study involving hundreds of participants to squeak out a small effect at the margins of statistical significance and this flies in the face of the stated claims of chelation therapists. CAM of all flavours typically comes to us with grand claims for dramatic effects for a patient to patient, day by day basis. Practitioners ‘know’ their therapy works because the effects are so obvious to them in their clinics. The properly stated hypothesis for a true study of CAM is not, ‘Does Therapy X have a detectable biological effect in patients’, but should be, ‘Does Therapy X have a large and reliable effect on patients [for objective measures of benefit]‘. This point is constantly obscured in the bickering over the minutiae of the outcomes of the many trials of CAM: if the claims for CAM were true such bickering simply could not occur.
Typo:
the plain fact is that it takes a study involving hundreds of participants to squeak out a small effect at the margins of statistical significance and this flies in the face of the stated claims of chelation therapists.
Also, as well as heparin having potentially relevant cardiovascular effects. Procaine is a Class 1A antidysrhythmic. So as well as having the chance of breaking blinding, it could have a small cardiovascular action relevant to the study. Perhaps, like the heparin, only a small action. The kind of small action that might only be revealed as effects in the margins of statistical significance if a trial was run in several hundred people. A trial, oh I don’t know, just like the TACT trial.
Who designed it?!
Yeah, I was going to mention this, but somehow didn’t get back to add it. Curiouser and curiouser. I’m not sure how much a weekly dose would matter, although maybe it would decrease the risk of arrhythmias in the immediate period after the chelation lowered calcium concentrations.
Here are explanations for the presence of heparin and procaine, quoted from Rozema, TC, “The Protocol for the Safe and Effective Administration of EDTA and Other Chelating Agents for Vascular Disease, Degenerative Disease, and Metal Toxicity.” (Journal of Advancement in Medicine Volume 10, Number 1, Spring 1997)
Note that Rozema is one of Lamas’s co-authors for the TACT presentation at the AHA meeting. He’s also a convicted felon.
Just to clarify, chelation therapy is still worthwhile in cases of actual heavy metal poisoning, correct?
This is also from Rozema’s “Protocol.” Pseudoscience at work (see our original critique for specific refutations of several of the claims):
What was their rationale for the ingredients in the chelation placebo? Would’t the best control be the same mixture of vitamins, procaine, heparin, etc. only without the EDTA? And why would they add dextrose?
Yes. We don’t know when those withdrawals occurred or why, but we suspect they had something to do with this.
@Kimball
Oy. That dose of heparin won’t cause significant systemic anticoagulation? What idiots. 5,000 U heparin is not a “small dose.” A typical loading dose of heparin these days ranges from 50-100 U/kg. 2,500 U, the amount of heparin in the infusion for the TACT protocol, is at the low end of the loading dose range for many women and lighter men. True, it’s given over 3 hours, and most loading doses of heparin are given over a much shorter period of time (say, 1 hour), but geez. These guys truly don’t know what they’re doing, do they?
Wow! Convicted for indecent assault (1962) AND felony extortion (1976)! Quite an accomplished fellow!
The chelation formula is very viscous; so they needed to add something to the placebo to increase its viscosity. Also, the vitamins in the chelation formula end up making the solution yellow. Dr. RW explains:
Even if the heparin were a small temporary amount as Rozema implies, it sounds like it is necessary to prevent local inflammation during infusion. They (the researches collectively) can’t justify its selective use out of necessity but then also brush off its unbalanced presence because it is too small to matter, unless there is a good reason to assume that the placebo fluid has no chance of causing inflammation.
He describes the procaine as being necessary for pain relief in some patients, but it sounds like it was given to all of the test group and none of the controls? That’s just mean.
@Dr. Atwood:
Thanks for the Rozema quote . I should’ve remembered the B6 bit – when penicillamine is used as a chelator to treat copper overload in Wilson’s disease, B6 supplements may be indicated as the penicillamine can bind and inactivate the B6. I can’t speak to an EDTA/B6 interaction, but that may be the truth grain buried in the nonsense.
B6 at 100mg doses can improve glucose tolerance in some individuals. The mechanism is unknown except that ~50% of body B6 is associated with liver glycogen synthase, for totally unclear reasons since it isn’t mechanistic. I wonder if some in the diabetic group was seeing an interaction with the B6 supplement.
I should think that all those megadoses would be activating secondary metabolic pathways that have nothing to do with their “chelation,” rendering the study even more suspect.
Here are the slides
http://www.slideshare.net/marilynmann/trial-to-assess-chelation-therapy-tact-slides
http://www.slideshare.net/marilynmann/tact-quality-of-life-outcomes
@ Duggan SC:
“Just to clarify, chelation therapy is still worthwhile in cases of actual heavy metal poisoning, correct?”
Absolutely. Children are monitored for elevated blood lead levels and all elevated blood lead levels are reported to the local health department for “intervention” and possibly for monitoring of chelation treatments:
http://www.cdc.gov/nceh/lead/ACCLPP/blood_lead_levels.htm
The most common cause of elevated blood lead levels is because youngsters are exposed to peeling paint and/or paint dust while an older home is undergoing renovations. In 1978, Federal law banned the use of lead in paint. There are other exposures as well, such as cosmetics brought into this country, lead paint on imported toys and lead used in glazes on imported ceramic plates and cups. Older homes also have lead solder on water pipes…in order to lessen the chance of lead being ingested, it’s prudent to NOT use the hot water tap to “start” boiling water for cooking purposes.
Chelation is also used for patients who have frequent blood transfusions, that result in “iron overload”:
http://www.cdc.gov/ncbddd/dba/chelation.html
Off topic, but
I had to make the observation that David Gorski looks quite a bit like the election hero of the day, Nate Silver*. My suggestion to David Gorski, a little dark hair wash and off the the closest liberal bar for free drinks tonight.
*Actually, He’s kinda SBM’s Nate Silver with bite.
@ mousethatroared: Actually Dr. Gorski and Nate Silver do have a lot in common…
http://en.wikipedia.org/wiki/Nate_Silver
“Silver was born in East Lansing, Michigan, the son of Sally, a community activist, and Brian D. Silver, a former chair of the political science department at Michigan State University.[9] Silver showed an interest and proficiency in math from a young age.[10] According to journalist William Hageman, “Silver caught the baseball bug when he was 6…. It was 1984, the year the Detroit Tigers won the World Series. The Tigers became his team and baseball his sport. And if there’s anything that goes hand in glove with baseball, it’s numbers, another of Silver’s childhood interests (“It’s always more interesting to apply it to batting averages than algebra class”).”[11]“
Lilady – Oh, I thought it was just a tendency to chose logical analysis over ideology…(and you know…the geek chic look) but the Detroit connection should work in the free drinks department too.
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