Trial to Assess Chelation Therapy

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http://scienceblogs.com/insolence/2016/06/02/unintentional-propaganda-f…

Been warning family members and friends not to go anywhere near chelation therapy.

When I saw the STAT article, I couldn't pinpoint exactly what was wrong about it. Until I realized the "Lone Scientist versus The Rest of The World" framing was just too cute to be credible.

The next logical step was easy: Head to Respectful Insolence as a learning experience in narrative deconstruction and proper interpretation of clinical trials.

In my opinion, STAT is a cozy place for stock salesmen to spread happy talk about speculations that maybe might some day perhaps - if we are lucky, and everything works perfectly every time - result in a product that makes someone a lot of money.

My advice is, clamp on your skeptic helmet before wading into that swamp.

I don't know. Most of the articles I've read on STAT have generally been pretty good. The only times I've really nailed STAT were over a credulous piece about Burzynski:

And the dreaded rat/cell phone/cancer study:

https://sciencebasedmedicine.org/no-a-rat-study-with-marginal-results-d…

Overall, I've generally found STAT to be pretty decent compared to most.

Not found: http://scienceblogs.com/insolence/2007/11/the_woo_aggregator.php

http://scienceblogs.com/insolence/2007/11/18/the-woo-aggregator/

alternative medicine therapists apparently haven’t stopped using it in patients without diabetes — though the trial found essentially no benefit in the broader heart disease population.

It's almost as if the whole project was just a lolly-scramble for lobbyists.

Depends on which Ologists are allowed to speculate on mechanisms, I guess. Cardiologists, who were long inclined to the plumbing model, assume that chelation cannot work. Endocrinologists are less certain. Don't you hate it when people are so nervy as to do small-s science on hypotheses you have already decreed should not be considered? And say, what if the diabetics-only trial is again positive? Will you then admit that there just might be a Mechanism to investigate, or will you continue to shout that everyone must ignore those results? (And will diabetics then assume that your bellowing against alleged side effects of vaccination, say, is equally unbiased? Trying to suppress evidence you don't like has a cost in public trust.)

@ jane #7: If you want medical researchers to spend time (gobs of it, research is time consuming) and money (gobs of it, research ain't cheap) then you have to have an idea what the mechanism is before you start, and the mechanism must be plausible using basic fundamentals of science as we already know them.

We already know that chelation therapy is very dangerous. It can cause life threatening electrolyte imbalances even when it is used for the only purpose for which it is currently medically indicated: heavy metal poisoning. So if you're going to use a very dangerous therapy for another purpose, you should be able to explain why it should work for that indication, and then you should obtain convincing results that it does in fact work for that purpose.

The TACT trial didn't do that. It wasn't a positive result, it was a negative result. So now you're demanding researchers conduct another trial on diabetics (a trial that is in fact going to be conducted) and you cry conspiracy theory when experts in the field express natural skepticism that a second trial is going to have different results?

There's this thing called ethics in research. The benefits must outweigh the potential risks. I don't that here; I don't see much of a benefit but I see tons of risk.

Unless there's a study out there showing some really amazing benefits to chelation (hint: as Orac points out, there is not), why would *anyone* take a chance (as Panacea points out) on screwing up a patient's electrolytes which can very quickly hurt or kill? Quacks have needlessly chelated children with autism and at least one child has died from this.

Sorry, Jane--there's too many downsides to chelation to make it worth the risk for no clear benefit.

Depends on which Ologists are allowed to speculate on mechanisms, I guess.

I vote for phrenologists.

Endocrinologists are less certain.

Do go on.

Oh, wait, it's Jane. Do goats really eat tin cans?

@10 Memories of a song I sang to my children ignoring their eye rolling...

Mary had a William goat, William goat, William goat,
Mary had a William goat,
Its stomach lined with zinc.

One day it ate an oyster can, oyster can, oyster can.
One day it ate an oyster can
And a clothesline full of shirts.

The shirts can do no harm inside, harm inside, harm inside,
The shirts can do no harm inside,
But the oyster can.

Ellie, that song demonstrates the nonsensical ravings of a lunatic mind.

Though, I have had a goat steal my Copenhagan snuff can only to bring it back slightly damaged. That very same goat would stand by your side and pee when I would -- He was careful to hike the leg the other way.

"The new heart patient asked Dr. Gervasio Lamas if he thought chelation therapy was worth a try. “Of course not!” the cardiologist replied emphatically. His Harvard training had taught him that alternative therapies were a waste of time and money, and potentially risky to boot. “I told him it was quackery.”...
Lamas was troubled by the idea that he had offered this man a medical opinion that wasn’t supported by science. And he decided to conduct a study himself."

How many times have we heard this story: "I was a skeptic about alt med, but I gave it a try anyway and boy, it really really works!"

The answer is no, you were always gullible, and it's quite understandable that you fell for quackery.

This tired mythic style of reporting drives me nuts. I see it in this form of brave maverick doctor or brave person failed by medical science and saved by some flavour of woo. Where did critical thinking and thoughtful reporting go? An obvious question that I have never seen in the media is why is the woo-meister getting away with charging tens of thousands of dollars for antibiotics? Last time I had some they were the cheapest meds in the pile. But no! can't ask the guru to justify that! Or even dig a little into the whole sorry scam industry. It is all brave unappreciated work at the fringes, unable to be appreciated for its greatness by the sheeple.

I'm reminded of a "brave maverick" physician story that had a substantially different ending. The reason was simple enough, good science from start to finish, despite his initial observations and study results being initially dismissed as nonsense until the actual results were reviewed.
Of course, the studies were initiated by the observation of an odd bacteria being found in lesions in several patients and when the physician looked at other patients similar lesions, the same bacteria was found.
He then began a study, which was initially derided as nonsense, but he countered with a valid physiological pathway where the bacteria and the lesions could be intimately related.
What followed next was rather unusual in modern science in two ways, one being what I consider rather bad science, the other, unusual.
He infected himself with the bacteria and developed the same types of bacteria infected lesions as his patients, which I consider rather bad science.
The unusual: He was absolutely right, H. Pylori causes certain types of common stomach ulcers, changing the treatment of an annoyingly common ailment.

Note the unusual characteristic, an observation lead to a theory, which was tested by a study, which unusually paid off with a genuine discovery.
Note that the "maverick doctor" was only a maverick in experimenting upon himself.

Brouchkov isn’t the only scientist analyzing ancient bacteria pulled from the frozen depths of the northernmost regions of the world, though he may be one of the only few doing so in search of eternal life.

http://motherboard.vice.com/read/meet-the-scientist-who-injected-himsel…

Otherwise, this place is dead as heaven on a saturday night...

If only there was a study where they tested the hypothesis in a population where hypercalcemia and hyperphosphatemia actually existed...
Oh wait, they did the EVOLVE study, where they tried to show that treating hemodialysis patients with hyperparathyroidism with cinacalcet reduced the rate of cardiovascular events. The results of the study were negative.
Design: http://cjasn.asnjournals.org/content/2/5/898
Results: http://www.nejm.org/doi/full/10.1056/nejmoa1205624#t=article

Disclaimers: I'm not a doctor. I was involved with EVOLVE as a site coordinator.

Jane @7

OK, so let's apply a bit of pretty basic chemistry here: what exactly is it that the chelating agents are removing from the body? That should be pretty easy to measure and demonstrate.

And then some pretty basic physiology: what physiological adverse effects are these supposed substances having? That should also be pretty easy to measure and demonstrate. And how are these effects in any way linked to a disease process? Which should also be pretty easy to measure and demonstrate.

Without those it is all a bit handy wavy and "Oh, look! A squirrel!"

The results of TACT 7 will show chelation therapy to be effective only for one particular patient in California named Bob. It will be declared a success.

Your tax dollars at work: New clinical trial of chelation therapy, new and old quacks enrolling patients

oracknows — Tue, 04 Oct 2016 01:33:23 +0000

Your tax dollars at work: New clinical trial of chelation therapy, new and old quacks enrolling patients

Whenever I refer to quackademic medicine and how the infiltration of quackery into medical academia has led to unethical clinical that are not only pseudoscientific wastes of money but potentially downright harmful to patients, two always come to mind. The first is the trial that tested the late Nicholas Gonzalez’s protocol for advanced pancreatic cancer, comparing it to standard-of-care chemotherapy. His protocol basically involves a combination of supplements (up to 150 a day), various vegetable juices, and, yes, the infamous coffee enema—several a day, actually. It’s basically a mystical, magical hodgepodge of woo that resembles the Gerson protocol. Yet, flush with enthusiasm for investigating implausible treatments of alternative medicine, the National Center for Complementary and Integrative Health (NCCIH), which was then called the National Center for Complementary and Alternative Medicine (NCCAM) approved the study based on a small case series of patients treated with the Gonzalez protocol whose seemingly fantastic results could easily be explained by selection bias. The trial was an absolute disaster, with patients treated with the Gonzalez protocol doing much worse than patients treated with standard-of-care chemotherapy, and that’s saying something given how poorly patients with pancreatic cancer do in general. Gonzalez made a lot of excuses, but those excuses couldn’t change the fact that a couple of million dollars had been wasted on a protocol that had no chance of working and patients in the Gonzalez protocol arm suffered unnecessarily.

The second example I use is, of course, TACT (the Trial To Asess Chelation Therapy), which makes the Gonzalez trial look tiny in comparison. After all, the NIH funded it for $30 million. When its results were finally revealed, they were, in essence, negative. There was no difference between any of the chelation groups in the composite endpoint that consisted of death, MI, stroke, coronary revascularization and hospitalization for angina, although here was one subgroup that showed a seemingly positive result: Diabetics. There was also a barely statistically significant benefit among those with a previous MI. However, there were no statistically significant differences in any of the individual events aggregated to form the composite endpoint, other than deaths among diabetics. Moreover, the result among diabetics was a result that could well have been spurious. So, in reality, the appropriate way to report the results was that chelation therapy doesn’t work, with the possible (slightly possible) exception of in diabetics, particularly diabetics with previous cardiac events. Overall, TACT is not particularly good evidence for an effect of chelation therapy on cardiovascular disease. Not surprisingly, Dr. Gervasio Lamas, the principal investigator of TACT, was very unhappy with all the criticism, and his responses were not particularly convincing.

So, of course, last week a press release was issued announcing that ~~Bride of TACT~~ Son of TACT—OK, TACT2—had been funded through a grant from the NIH, including NCCIH and the National Heart, Lung, and Blood Institute (NHLBI). Naturally, I was not pleased. I was also disappointed that Dr. Josephine Briggs had betrayed the promise in NCCIH’s last two strategic plans to do some real science for a change by allowing NCCIH to contribute to this grant. More importantly, what the hell was the leadership of NHLBI thinking? I expect nonsense like this from NCCIH, but not from NHLBI. Whatever the rationale, what TACT2 proves is that in quackademia, pseudoscientific clinical trials never die. Like Jason Voorhees, Freddy Krueger, and Michael Myers, just when you think they’re dead, they return from the dead. So it is with TACT2.

Be that as it may, although I mentioned it in passing, there was one aspect that I didn’t cover sufficiently in my last post. That was mainly because I didn’t have the tools then. I’m referring to the quack clinics that enrolled patients on TACT the first time around and how at least some of them had compromised blinding. In any case, back then, Dr. R. W. Donnell noted that only 12 of the 110 study sites were located at academic medical centers and that a substantial number were basically quack clinics peddling pseudoscientific health claims and practices. He even did what he called a “magical mystery tour” of some of these clinics, which included, for example, the Marino Center for Progressive Health in Cambridge, Massachusetts, which featured acupuncture, chelation and chiropractic, and an IV therapy program that offers intravenous therapy for multiple ailments. Another center, Innovative Medicine in Lafayette, IN, offered chelation therapy, hyperbaric oxygen, “advanced thyroid replacement”, chiropractic, acupuncture and “multiple powerful intravenous therapies.” They also claim that chronic neurologic diseases of any type usually respond to hyperbaric oxygen.

Given this background, I wondered: Is the same thing happening with TACT2? Then a reader pointed out that there is a website for TACT2 looking for clinical sites for the trial. It also has a map with current TACT2 sites. This time around, I’ll note that more university sites are available, including Stanford University, Baylor St. Luke’s in Houston, Johns Hopkins Bayview Medical Center, the University of Ottawa Heart Institute, and Universith Hospitals of Cleveland, the latter of which saddened me greatly, as that’s where I did my surgery residency.

However, the overwhelming number of TACT2 sites are not academic medical centers, and, now as it was 10 years ago, there are already a lot of quack sites enrolling patients for TACT2, so many that I’m already tempted to do my own version of Dr. Donnell’s magical mystery tour from a decade ago. So the first thing I did was to look to see if any of the same sites featured by Dr. Donnell as TACT sites have signed up for the sequel. The first one I found, unfortunately, was the Born Clinic, which was a TACT site and is now a TACT2 site. It offers chelation therapy (of course), as well as acupuncture, prolotherapy, thermography, and other dubious treatments. It’s actually one of the “less bad” clinics.

The Magaziner Center for Wellness in Cherry Hill, NJ is another TACT site that’s re-upped for TACT2, as well. Dr. Donnell noted that the Magaziner Center offered “a variety of alternative treatments including hyperbaric oxygen therapy for neurologic diseases.” Guess what? Ten years later, it still does:

HBOT is prescribed for conditions such as cancer, Lyme disease, ADD/ADHD, stroke, migraines, autism, chronic fatigue, multiple sclerosis, cerebral palsy, Parkinson’s disease, Alzheimer’s disease, Crohn’s disease, Bell’s palsy, carbon monoxide poisoning, excessive blood loss, gangrene, radiation necrosis, diabetic foot ulcers, severe anemia and much more.

Of note, Dr. Allan Magaziner has written books like The All-Natural Cardio Cure: A Drug-Free Cholesterol and Cardiac Inflammation Reduction Program and Chemical Free Kids: Safeguarding Your Child’s Diet and Environment. (Here’s a hint: It’s impossible to make kids “chemical-free.”) He also brags about being cited in books by Suzanne Somers’, which, to be honest, is not something I would ever brag about. He’s also a past president of American College for Advancement in Medicine (ACAM), an organization that Kimball Atwood quite accurately referred to as the “mother of all pseudomedical pseudoprofessional organizations” and part of the house that Laetrile built. In other words, it’s the quack organization to end all quack organizations.

Another familiar name comes up, although I don’t recall if his was a site used in the original TACT. He’s on board for TACT2, though. His name is Michael Schachter, and he’s been practicing cancer quackery since at least the 1970s. It’s how he still treats cancer:

Treatment options at the Schachter Center include detoxification, dietary protocols, and nutritional supplements that enhance and support the immune system and the healing process. Oral supplements include: vitamins, minerals, enzymes, herbs, phytonutrients, and other nutritional supplements. Intravenous hydrogen peroxide and/or intravenous infusions of high doses of vitamin C are often recommended. We frequently recommend other natural substances that appear to have some anti-cancer properties, for certain patients.

Extensive testing may be done to evaluate nutritional status (direct or functional vitamin tests, serum coenzyme Q10, red blood cell minerals), heavy metal toxicity (provoked urine tests for mercury, lead, and others), the status of the liver’s detoxification mechanisms, hormone status (DHEA levels, basal temperatures for thyroid function, and others) and immune status (Natural Killer Cell functional activity). Of course, standard tests such as a complete blood count, liver chemistry tests, and blood cancer markers are routinely ordered, especially if they haven’t been done recently.

We also utilize the innovative, non-toxic, biological compounds developed by the late Dr. Mirko Beljanski, and have recently added therapies utilizing vitamin D, vitamin K2, Salvestrols, balancing lipids, the use of iodine and important dietary changes. The value of exercise is also stressed.

Yep, it’s all there: “detox” quackery, “boosting the immune system,” intravenous peroxide, high dose vitamin C, provoked urine tests, and more! (He even offers reiki.) And this is the sort of guy that Dr. Lamas is going to trust to sign up patients for TACT2? Apparently so, even though his website includes a Quack Miranda Warning.

That’s not all, though. Here’s another center that’s signing up patients for TACT2, Delaware Integrative Medicine, fronted by Dr. Henry Childers IV, FAAO, who describes himself as “board certified in General Surgery, and Cardiothoracic Surgery, with advanced certificates in both FSM and ozone therapy,” a “fellow in the American Academy of Ozone Therapy” and “co-investigator on the Health and Human Services Institutional Review Board Ozone efficacy research study.” I groaned when I read that. Damn. A fellow surgeon, but turned to quackery. Indeed, he peddles something he calls “cellular medicine” (whatever that is), complete with impressive woo babble (like technobabble in Star Trek but with woo):

Cellular medicine works by harnessing the body’s innate ability to grow and heal itself without all the drugs and invasive procedures that have become so prevalent in medicine today. It is effective because it works on the cellular level by stimulating gene expression, enhancing cellular metabolism, improving oxygen utilization, increases cellular detoxification including up-regulating hundreds of antioxidant’s response elements. Treatments such as Ozone Therapy can induce a rearrangement of the biochemical pathways, thereby activating second messengers in a cascade with a multiple system action.

Cellular medicine dramatically increases ATP and protein synthesis –all which improve cellular function. Treatment results in a dramatic decrease in pain and inflammation while increasing blood supply and growth factors. These cellular changes, and the resulting repair and regeneration of injured tissue leads to organ and consequently total-body wellness. Our cells and tissues function like they did when we were in our 20s.

According to his website, Dr. Childers offers everything from chelation therapy to ozone therapy to ultraviolet blood irradiation to all manner of “detoxification” quackery. He even offers something he calls “Chela-zone Therapy,” which is:

Chela-zone therapy consists of a combination of chelation therapy and ozone therapy and greatly enhances the already well-documented efficacy of chelation therapy. Chelation therapy improves circulation, enabling more oxygen to reach the cells. Ozonotherapy enables the cells to use the oxygen that is being delivered with a much higher level of efficacy. The two modalities are truly synergistic, and the results of either a greatly increased when they are administered together. For this reason, in most clinical situation, we prefer chela-zone treatment over chelation therapy alone.

Because, why not combine the two? In woo world, quacks always find a way to combine two different pseudoscientific treatments? One wonders how Dr. Childers can sign up patients for TACT2 if he believes combining chelation therapy with ozone therapy is superior to both.

Best not to ask questions.

Here’s what I see happening. TACT2 is an utterly unnecessary study that, in pursuit of “proving” that an alternative treatment “works,” will waste $37 million of my taxpayer dollars following up on a result that was almost certainly spurious. In the process, it will expose high risk diabetic patients with cardiovascular disease to a potentially dangerous treatment, with no good reason to expect that it will benefit them. Yes, it will be somewhat better than TACT in that there do appear to be more academic institutions on board this time around, but there are also a lot of quack clinics, some of which are the same quack clinics that participated in the original TACT study.

In conclusion, TACT2 is, just like its predecessor, a profoundly unethical study rooted in pure pseudoscience and quackery. Although the proportion of study sites at academic medical centers will be much higher than in TACT,, most likely thanks to the proliferation of quackademic medicine in the decade since the original TACT study was getting under way and the effective spin of a negative or spurious result into a "positive" one, they will nonetheless still be a relatively small minority in TACT2 and there are already a fair number of quack clinics that have registered as TACT2 study sites. Indeed, I can’t help but wonder which institutional review boards (IRBs) approved these studies, given that these “integrative” medicine clinics almost certainly don’t have IRBs of their own. It’s sometimes said that insanity is doing the same thing over and over and over and expecting different results. By that definition, TACT2 is insanity. I also expect that its results will be basically the same as TACT: A subgroup showing an apparent benefit and possibly a barely statistically significant result. (I hope I’m wrong, but I’d put money on this.) This will then lead to another $37 million or more for the mandated followup trial to chase after a supposedly positive result.

Quackademic medicine marches on. Maybe I’ll have to keep an eye on the TACT2 website and check out some of the clinics signing up patients. I’ve barely scratched the surface, and I expect more quacks will be joining the study. In fact, I’d be surprised if they didn’t.

oracknows Mon, 10/03/2016 - 21:33

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http://www.salon.com/2016/10/02/is-the-dea-high-the-agencys-emergency-b…

the late Dr. Mirko Beljanski

What a surprise! He died of cancer.

the late Dr. Mirko Beljanski
What a surprise! He was a vile scamming sh1weasel!

It doesn't surprise me that Dr Magaziner is a TACT proponent. He's very fond of any and all kinds of woo for which he can perform a thorough walletectomy on his marks...er....patients.

@ herr doktor bimler

the late Dr. Mirko Beljanski

** reading the wiki article **
Uh, he was treating French President Mitterrand for his cancer? I never knew.

** switch to the French version of the wiki article, much longer **
Lots of background. A scientist who started well and then went spiraling down the rabbit hole.

Bit frightening, all of these untested plant extracts his relatives are selling.
Among the basis for the rejection of his drugs by the authorities, some are extracted from a Brazilian plant, except that the name could designate half a dozen plants, and at least two of them are full of highly toxic alkaloids.
Clinical trial in Montpellier: 2 patients.

Oh, Luc Montagnier likes him. And Beljanski's plant product is working, not because of its impeding action on DNA replication (Beljanski's rationale - his life's work was about discovering DNA or RNA transcriptases and retro-transcriptases), but because it's an antioxidant, and also boosting the immune system.
Stop helping, Luc.

** check the wiki references **
Oh joy, more French woo.

What a surprise! He died of cancer.

Let's be fair, at that point he didn't have access to his drugs anymore (at least whose produced in France).
OTOH, when he was treating my former president, who nonetheless died of his cancer...

University of Ottawa Heart Institute

Granted the rules may be different for NIH, but NSF and NASA do not allow direct funding of researchers at non-US institutions. Is NIH's Canadian counterpart contributing to this farce? Perhaps one of our Canadian readers could comment.

I also have to ask whether these non-academic clinics have IRBs, or whether the PI's institution covers that for them.

A credulous local TV reporter named Emily Lampa has done several stories attempting to legitimize fake "chronic lyme" diagnoses. Henry Childers is (or was) a "lyme literate" quack and member of the rogue organization ILADS.

She interviewed some of Henry Childers's patients as they were receiving intravenous ozone treatment. The bill was supposedly $9,000 (out of pocket) for a course of treatment. The few minutes of interviews are textbook examples of how quackery works.

One patient believes waxing and waning of pain means the ozone is working: "There's been a lot of ups and downs and that’s been frustrating but I know it's working because I wouldn't have those ups and downs of it wasn't doing something."

Childers writes off the idea that it might be a placebo effect: "I don't like anecdotal data but when you treat people who have had decades or years worth of symptoms, debilitating that affect every aspect of your life and all of a sudden it's getting better who cares? They’re getting better. It’s not any voodoo stuff. It’s just open up the biochemistry book. It's all in there."

Lampa posted the full interviews with the patients, where you learn more about their stories. It turns out that a lot of the stories are questionable. For example, one patient was initially diagnosed by a psychic "medical intuitive".

The reporter notes how protective the patients are of Childers, how they will do anything to protect him from being prosecuted.

I might have to take a closer look at Dr. Childers sometime in the near future, maybe one day when there's nothing in the news interesting enough for me to blog about. His "Chela-zone" therapy is a form of quackery I've never encountered before.

Cellular medicine dramatically increases ATP and protein synthesis

I'm pretty sure this is what the Incredible Hulk relies upon. I always thought all that gamma-ray malarkey was a bunch of a lies.

I cannot help it, but every time I see the words chelation therapy , especially in connection to CAM, woo, etc., I catch myself thinking "cheating" therapy.

As I used to say, they don't call it "cheat-lotion" for nothing. :-)

As I used to say, they don’t call it “cheat-lotion” for nothing.

Perhaps since coopted by cosmetic creams formulated from "vegan stem cells."

That was interesting. I visited the page and found this howler after reading the FDA warning. http://www.annmariegianni.com/our-promise-truth-in-labeling/

I'm not an expert on statistics, so I'm asking when a study fails to meet its endpoints, but a post hoc analysis finds a statistically significant result in a subgroup, is it really possible to assign a p-value?

I’m not an expert on statistics, so I’m asking when a study fails to meet its endpoints, but a post hoc analysis finds a statistically significant result in a subgroup, is it really possible to assign a p-value?

IANAEOS either, but sure. As always, the question is whether they mean anything.

Mark@13: There is a reason Mark Twain classified untruths into three categories: lies, damn lies, and statistics. Or to put it another way: Figures can't lie, but liars can figure.

One of the things about post-hoc analyses is that it becomes tempting to torture the data until it confesses. I can't say for sure whether that happened in this case, but it is good reason to be skeptical.

Your tax dollars are also going to double deaths due to fouling access to a natural herb, kratom, in favor of pharmaceutical companies raping the alkoloids for patents and profits. There is an opiod epidemic in this country -- Heckuvajob Chucky (Rosenberg).

The ban on kratom — a safe and popular treatment for chronic pain, depression, anxiety and PTSD — is inexplicable

I looked into kratom when I heard on the impending ban. The liver toxicity issue is scary enough that the ban seems reasonable.

I read the Salon article. The author clearly doesn't know what he's talking about. Kratom is not safe. Raw opium is safer.

The liver toxicity issue is scary enough that the ban seems reasonable.

I'd say that needs a citation.

In memoriam of PgP, whose wet leprosy colony doesn't allow internet access, I've now finally visited Reddit.

https://www.reddit.com/r/kratom/

The liver toxicity issue is scary enough

And yet, tylenol/acetaminopen/paracetemal which is the #1 cause of liver failure in the U.S. is not banned.

Gilbert, you're so far off topic you're not even in the same section of the alphabet.

What does this have to do with chelating diabetics to treat heart disease?

He's hijacking the conversation to complain he can't get access to his dope legally anymore.

Gilbert, the difference between kratom and acetaminophen is the latter is produced under controls that maintain consistency in dosing and quality, and that dosing is well understood. If you stay within dosing guidelines, you are unlikely to injure your liver.

With kratom, you don't know from one dose to the next how much of the active ingredient you're getting, how pure it is, and no one knows how much is actually safe to consume. Without controls, you don't know whether or not your dope is contaminated with something nasty . . . like heavy metals.

You wouldn't want to end up need chelation therapy now, would you?

You should know by now that everything with Gilbert is about him wanting to get high.

Not that there is anything wrong with that, but it gets boring.

https://petitions.whitehouse.gov/petition/please-do-not-make-kratom-sch…

I've never used it but I recognize big pharma corruption when I see it.

and that dosing is well understood. If you stay within dosing guidelines, you are unlikely to injure your liver.

Ohh. But what happens to the 'guidelines' if one happens to concurrently ingest alcohol? ****fuck**** those people who should'v known better from the warning that still doesn't exist.

and that dosing is well understood. If you stay within dosing guidelines, you are unlikely to injure your liver.

Ohh. But what happens to the 'guidelines' if one happens to concurrently ingest alcohol? Intercourse*** those people who should'v known better from the warning that still doesn't exist.

*** And by 'intercourse' i mean F... You.

Gilbert, this post is not about kratom. Your hijacking the thread is not appreciated. Knock it off. I'm putting you into automatic moderation. Any posts that are about kratom will not be approved.

Quelle surprise, Orac. I expected this from pharma shills.

"FSM and ozone therapy?" So their treatments involve petitioning for the healing touch of His Noodly Appendage too?

@ Anonymous Coward

All treatments should involve His Noodlynes, for he Touches All!*

* Whether they like it or not!

" Quelle surprise"

Pro tip:
If you're going to insult Orac**, you should AT THE VERY LEAST be original enough not to steal an idiom he uses frequently in doing so. Seriously.

** not that I think that anyone should insult Orac but it's the principle of the thing!

" for he Touches All*

* Whether they like it or not"

Yeah, tell me about it.

I have a coworker who used HBOT (among other things, mostly SBM) after a massive head injury. I guess it wasn't covered by insurance because she complained that the cheapest place to get it done was a quack's office where one day a patient came back into the waiting room while still "steaming her hoo-haa". (Complete with tubing.)

So while there's a time and a place for HBOT, it also seems to be a warning flag of serious wackiness.

You don't 'steam' a hoo-haa; You scrub it out with pine cones and donkey fat.

you should AT THE VERY LEAST be original enough not to steal an idiom he uses frequently

Sorry, Denice Walter. It was the only sufficiently mocking thing that I could come up with in short order before the 'moderate' kicked in.

Raw opium is safer.

What an ignorant, assinine statement**. It's good Orac ran interferrance for you, Mark Thorson, before you need feel the sting and stink of being a dirty floor mop.

People are using it in lew of other substances, illicite and pharmaceutical. It is breaking people's addiction to opiates, methamphetamine, and alcohol. It takes away people's pain. It has a mild elevating effect like coffee; Which is not surprizing because this dangerous plant is in the coffee family.

I certainly see how it is a threat to drug company profits -- Most of the current 'epidemic' is due to pharma's promulgating their tylenol-poisoned pain pills and oxycontin; Now they want to pretend to clean up the mess with more patented offerings. Your duckspeak and misinformation is going to destroy untold many lives; Not just prison time, but in amplified addiction and its' concomitant fatality.

Kratom wrecks your liver. Opium is protective. The ban is fully justified.

Chronic use of kratom recreationally has been associated with rare instances of acute liver injury.

https://livertox.nih.gov/Kratom.htm

Most people don't use it 'recreationally' as there is not much of a high there other than like caffein (which accounts for thousands of poison control calls per year). Also, no one has died from said liver injury -- the 15 world-wide recorded deaths** all involved other substances or adulteration; Usually with things approved by the FDA such as Tramadol homologs. The DEA admits this. Also, ****** does not cause one to take a break from breathing as opiates do.

Do you have a citation for said prevelance of liver injury or death thereof? I did not think so. So why do you insist it is terrible for the liver? Is it just *assumed* on your part? You obviously discount 'harm reduction' when it comes to pain, addiction, or depression and how it relates to deaths.

** In 2014, there were 458 Tylenol deaths in the US and thousands of liver injury and its' attendant health problems.

Acetaminophen overdose sends as many as 78,000 Americans to the emergency room annually and results in 33,000 hospitalizations a year, federal data shows. Acetaminophen is also the nation’s leading cause of acute liver failure

http://www.huffingtonpost.com/2013/09/24/tylenol-overdose_n_3976991.html

Ok. I grant you that opium is kind on the liver. However, it is not currently legal. And there is that whole taking a break from breathing thing with an OD.

Orac did not approve the comment I posted of the statistics on the hundreds of thousands of ER visits or the 458 liver failure deaths a year from tylenol** -- It doesn't matter if it is used 'within the dosing guidelines' as there is still a great human toll due to it.

There are thousands of admissions due to caffeine -- not banned
There are thousands of admissions due to alcohol -- not banned

Would a ban on coffee and daqueries not fit in with your plans, Mark Thorson?

I'd still like to see a citation backing your claim that brand X 'wrecks your liver'.

**His portfolio may be a little bit to heavy on McNeil Consumer Healthcare and/or Johnson & Johnson.

In that case, I understand completely and my condolences are offered.

"You should know by now that everything with Gilbert is about him wanting to get high."

LoL Johnny. Well if you call drinking a couple cups of coffee *getting high*. The DEA is wrongheaded on this for some reason. There is no " imminent hazard to public safety", the stuff has been sold in the states for decades.

https://lookaside.fbsbx.com/file/Hogan%20Lovells%20Letter%20Regarding%2…

“You should know by now that everything with Gilbert is about him wanting to get high.”

LoL Johnny. Well if you call drinking a couple cups of coffee *getting high*.

You know, Timmeh, you were doing so well sticking to the "Gilbert" pseudonym. I mean, I didn't agree with the original sentiment, but that largely involves having an even lower opinion of you.

So, now, "sullenbode" joins "Mitzi Dupree" and the rest. (Were you also "Clayton Bigsby"? I've only recently started having to categorize the script entries.)

Lol Narad. "Mitzi Dupree" is a Deep Purple song--

she said hi i am mitzi
the queen of the ping pong
where you going boy
i said nowhere
she said i'm movng on
i thought what is this
i cannot resist
here she is
and i've always wanted a girl
with a name
a name like mitzi dupree

You don't get out much, do you Narad?

I found this article very interesting as well. It is about toxic and carcinogenic components in skincare products
https://www.zayaoils.com/blogs/blog/18838755-5-more-reasons-to-use-100-…

The liver toxicity issue is scary enough that the ban seems reasonable.

I'm still waiting for that citation, Mark Thorson #17. Ohh, no citation? Perhaps it is because you were thinking of kava kava?

With a little help from its friends, NCCIH funds Son of TACT to study chelation quackery again

oracknows — Thu, 29 Sep 2016 04:30:59 +0000

With a little help from its friends, NCCIH funds Son of TACT to study chelation quackery again

One of the things that first led me to understand the dangers of quackademic medicine was a trial known as the Trial to Assess Chelation Therapy, or TACT. Chelation therapy, as you might recall, is the infusion of a chelating agent, or a chemical that binds heavy metals and makes it easier for the kidney to secrete them, in order to treat acute heavy metal poisoning. Unfortunately, quacks of all stripes have latched on to chelation therapy to treat a number of diseases and conditions. For instance, antivaccine quacks like to use chelation therapies to treat autistic children using the rationale that their autism is a manifestation of “vaccine injury” due to the mercury in the thimerosal preservative that used to be in several childhood vaccines. The evidence is overwhelming that mercury in vaccines is not associated with autism, but that is one of the two pseudoscientific beliefs behind the belief by antivaccinationists that vaccines cause autism, the other being that the MMR vaccine somehow causes autism. Of course, thimerosal was removed from vaccines nearly 15 years ago, but that never stopped autism quacks from continuing to use it as a part of “detoxification.” Never mind that, because of its ability to reduce the concentration in the blood of critical minerals like magnesium and calcium so much that heart rhythm disturbances result, chelation therapy is potentially dangerous and at least one child has died due to chelation therapy. Once latched on to, quackery is never abandoned.

I’m not actually going to discuss chelation therapy for autism (due to “vaccine injury,” according to antivaccine activists), though. It turns out that the other major use of chelation therapy in alternative medicine is to treat heart disease, the rationale being that there is calcium in some atherosclerotic plaques, the thought being that you could chelate the calcium out and cause the “softening” and regression of these potentially life-threatening plaques. Unfortunately, it doesn’t work that way, but that didn’t stop chelationists from Gish galloping away with ever more fanciful and less plausible explanations about how chelation “works.” Not only is chelation therapy implausible based strictly on chemistry and stoichiometry, but there is no good evidence that it actually causes regression of atherosclerotic plaques.

Sadly, none of this stopped believers from undertaking a large, multi-institutional study of chelation therapy for cardiovascular disease. Thus was TACT born. Kimball Atwood wrote the definitive explanation as to why TACT was unethical, bad science, and highly unlikely to produce usable results way back in 2008. You really should read the whole thing for background, but among the reasons given by Atwood included:

At least 30 deaths associated with chelation since the 1970s, while not one death is noted in the TACT literature.
TACT was promoted mainly by a group called the American College for Advancement in Medicine (ACAM), a highly dubious organization devoted to the promotion of alternative medicine.
The study was rejected by 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), now known as the National Center for Complementary and Integrative Health) 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.
There were no good animal studies or human phase I or II trials to support doing such a large multicenter randomized, double blind, placebo-controlled clinical trial.
TACT included nearly 100 “chelation site” co-investigators who were unsuitable to care for human subjects or to report trial data. Most espoused (and continue to 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 three were convicted felons. Dr. R. W. Donnell once did what he called a “magical mystery tour” of several of the TACT sites. Basically, they were quacks.Only 12 of the 110 TACT study sites were academic medical centers, and many of the study sites were highly dubious clinics touting even more dubious therapies, including heavy metal analysis for chronic fatigue, intravenous infusions of vitamins and minerals, anti-aging therapies, assessment of hormone status by saliva testing, and much more. Dr. Donnell also points out that the blinding of the study groups to local investigators was likely to have been faulty.

Unfortunately TACT marched on. Over $30 million later in 2012 its results were revealed. Let’s just say that they were...underwhelming. You can read the details in the two links I just listed, but the CliffsNotes version is this. TACT tested chelation therapy versus placebo. Actually, it was more complicated than that. The TACT study was set up with a 2 x 2 factorial design:

Chelation plus high oral high dose vitamin and mineral supplement
Chelation placebo plus oral high dose vitamin and mineral supplement
Chelation plus oral high dose vitamin and mineral supplement placebo
Chelation placebo plus oral high dose vitamin and mineral supplement placebo

The regimen was described in detail in an earlier publication. The vitamin supplements included doses ranging from 25% to 6,667% of the RDA for various vitamins. For example, the dose of vitamin C was 2,000% of the RDA; thiamin, 6,667%; and vitamin A, 500%. The previous presentation looked at the chelation therapy aspect of the study. This study looks at the oral high dose vitamin and mineral supplement treatments.

Now let’s get to the results. They were, in essence, negative. There was no difference between any of the chelation groups in the composite endpoint that consisted of death, MI, stroke, coronary revascularization and hospitalization for angina. There was only one subgroup that showed a seemingly positive result: Diabetics. There were no statistically significant differences in any of the events aggregated to form the composite endpoint, including among diabetics. It was a result that could well have been spurious. So, in reality, the appropriate way to report the results was that chelation therapy doesn’t work, with the possible (slightly possible) exception of in diabetics, particularly diabetics with previous cardiac events. In reality, given the extreme implausibility that chelation therapy has any therapeutic effect against atherosclerotic heart disease based on chemistry, the most parsimonious interpretation of TACT is that it was a negative study. Unfortunately, my saying so led to some rather harsh attacks against me, with one characterizing criticism of the results of TACT as “shrill and brutish.”

So, after wasting $30 million funding a sham of a study, what’s next? I note that when Steve Novella, Kimball Atwood, and I met with Dr. Josephine Briggs, the director of NCCAM, in 2010, one of the things I remember most about our conversation was the discussion of TACT. Basically, Dr. Briggs did everything she could to distance the herself from TACT, pointing out that it was funded before her tenure as director began and it had been turned over to NHLBI, in essence shutting down conversation about just how unethical and pseudoscientific the study was from its very inception.

Apparently times have changed, because the other day there was a press release announcing that the NIH is funding TACT2. Yes, there will be a sequel to the misbegotten, unethical mess of a study that was TACT. The Son of Frankenstein rises again. And how much will it cost? Let’s go to the press release:

The National Center for Complementary and Integrative Health (NCCIH) of the National Institutes of Health (NIH) has awarded $37M to Mount Sinai Medical Center of Florida and the Duke Clinical Research Institute to initiate the second Trial to Assess Chelation Therapy (TACT2). The trial is also co-funded by the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Environmental Health Sciences.

TACT2 will examine the use of intravenous chelation treatments in combination with oral vitamins in diabetic patients with a prior heart attack to determine if they reduce recurrent heart episodes, such as heart attacks, stroke, death, and others, by removing toxins from the blood. Chelation is a process by which a medication, such as edetate disodium (Na2EDTA), can "grab" and remove toxic metal pollutants - like lead or cadmium - which are present in most individuals.

Ah, yes. Spread the blame around by having more than one institute and center in the NIH fund the thing. Can you say “plausible deniability” for each institute? Sure, I knew you could. Apparently Dr. Briggs, for all her effort to distance herself from what she appeared (to us, at least) to know was, scientifically speaking, a flaming pile of fetid dingos’ kidneys, has either had a “come to Jesus” moment, swallowed her scientific credibility, and drunk deep of the Kool Aid. After all, there’s no way a study this big gets funded without the directors of the relevant centers and institutes all signing off on it, which means Dr. Briggs must personally have signed off on this study. Yes, these studies do go through peer review in NIH study sections, but there is a second tier of review, where final decisions are made regarding what grants to fund. These rely heavily on the study section findings, but for very large grants the relevant directors will definitely need to sign off. And, make no mistake, $37 million is a very large grant indeed. By way of comparison, a typical R01 is on the order of $1.25 million plus indirect costs, which still leave it under $2 million.

So let’s see how the Mount Sinai Medical Center of Florida is spinning this in its press release:

"If TACT2 is positive, it will forever change the way we treat heart attack patients and view toxic metals in the environment," said Lamas. "Therefore, with NIH support and in collaboration with the Duke Clinical Research Institute, Columbia University, New York University, Mount Sinai (NYC), and hundreds of physicians and nurses throughout the U.S. and Canada, we are moving forward with TACT2."

A one-year planning phase for TACT2 was conducted and included finalizing the research protocol for the trial as well as gaining NIH approval. During this phase, the investigators also identified over 100 clinical research sites in the US and Canada that aim to enroll 1,200 cumulative patients in the trial.

Yes, Dr. Lamas is deluded enough to think that it would be a good thing if quackery like chelation therapy becomes accepted. That’s how far down the rabbit hole he’s gone. He also thinks that it would be a good idea to spend even more than what was spent on the original TACT trial on a sequel that is not scientifically indicated.

Seeing this press release, I was curious. So I went to the RePORT website and found what TACT2 entails:

The purpose of the Trial to Assess Chelation Therapy 2 (TACT2) is to perform a pragmatic and efficient replication of TACT1 in patients with diabetes and a prior heart attack.

OK, stop right there. Whenever I hear the term “pragmatic” applied to a clinical trial, my skeptical antennae start twitching. As I’ve described so many times before, “pragmatic” means “in the real world.” Here’s the problem. Pragmatic trials can be useful, as they can give an indication of how well a treatment might work “in the real world” or “on the ground” or whatever analogy you want to use to describe taking an effective treatment and applying it to real patients. However, you have to show that a treatment is truly efficacious before a pragmatic trial can be justified.

But let’s check out the rest:

The results of this trial will determine whether disodium ethylene diamine tetraacetic acid (Na2EDTA) chelation therapy receives approval from the US Food and Drug Administration (FDA) and is subsequently accepted to reduce the risk of major adverse events from coronary artery disease (CAD) in patients with diabetes. TACT2, if positive, will also promote research into the mechanism(s) of benefits and provide novel insights into the pathobiology of CAD. The Trial to Assess Chelation Therapy (TACT1) was developed in response to a Request for Applications from NCCAM and the National Heart Lung and Blood Institute (NHLBI) to address the concern that chelation use was widespread but there were no reliable data on either safety or efficacy.

Holy hell. Just because a lot of quacks are using chelation therapy does not mean that there has to be a study! After all, there aren’t even any good animal studies to support the use of chelation therapy. In general, the progression of evidence goes from cell culture to animal studies to early human clinical trials to phase 3 clinical trials. Then, only then, is a drug approved for use. In any case, let’s look at the design:

The three Specific Aims of TACT2 are: 1) To determine if the chelation-based strategy in patients with diabetes and prior MI improves event-free survival; 2) To determine if the chelation-based strategy in patients with diabetes and prior MI reduces mortality; 3) To perform a cost-effectiveness analysis of the TACT2 chelation strategy. TACT2 will enroll 1200 diabetic patients 50 years of age or older with a prior MI and a serum creatinine of 2.0 mg/dL or less. Patients will be randomly allocated (1:1) to receive either chelation + OMVM or double placebo and followed for clinical events until the end of the 5 year trial. The primary endpoint will be a composite of all-cause mortality, recurrent MI, stroke, coronary revascularization, and hospitalization for unstable angina. A Clinical Events Committee masked to treatment assignment will adjudicate events. Principal secondary endpoints will include: (1) all-cause mortality; (2) a composite of cardiovascular mortality, recurrent MI, or stroke; and (3) safety.

Here we go again. Instead of looking at “hard” (i.e., objective) endpoints like all cause mortality, recurrent MI, and stroke, TACT2 will be looking at the same composite endpoint that includes endpoints with a lot of judgment behind them, such as hospitalization and the need for coronary revascularization. If Dr. Lamas were truly serious about determining if chelation therapy worked, he’d drop the composite endpoint and look only at all cause mortality, myocardial infarction, and stroke as primary endpoints without creating this Franken-endpoint.

I realize from my previous discussions of TACT that other cardiology studies have used composite endpoints, and such endpoints are not uncommon in cardiology clinical trials, but that does not mean I accept them. Let’s just put it this way. composite endpoints are not in general a good thing. There’s a way but they can be made less bad, so to speak, by not including subjective endpoints like coronary revascularization and hospitalization, both of which are subject to a great deal of clinical judgment in deciding who requires them. More problematic is the variation in usage of such interventions that has nothing to do with whether the treatment works or not. For instance, in the state of Michigan, there is up to a 2.4-fold variation in rates of percutaneous coronary interventions (PCI; i.e., angioplasty) between the highest use and lowest use areas. That’s just one state. Similar studies have shown wide variability in coronary revascularization rates just on geography alone. Adding such a variable to a composite endpoint is thus a bad idea on a scientific basis alone. At best, it adds unnecessary variability to the composite outcome measure for no useful benefit; at worse it adds significant bias, particularly if subjects being treated in academic centers, where patients are more likely to be referred for appropriate coronary revascularization interventions were in areas with significantly different PCI usage rates than areas where subjects being treated in “complementary and alternative medicine” (CAM) centers, where one might reasonably expect that referral for revascularization might be a bit less—shall we say?—expeditious. I could see a composite endpoint in which the components were all “harder” endpoints, such as the triple endpoint of death, nonfatal MI, and nonfatal stroke, but even such endpoints are not without problems.

In the end, you and I (at least those of us in the US who pay taxes) are funding an even larger boondoggle of a quackademic study than TACT was in the form of TACT2. I predict (as Atwood did for TACT) that TACT2 will be just as large of a fiasco as TACT was, particularly if the same centers are used to recruit patients for it. Unfortunately, I also predict that it will, like TACT, end up appearing to be “positive” enough to “justify” the next study. Remember, if you look at objective endpoints only, TACT was actually resoundingly negative. It took the composite endpoint to make it appear positive.

My final word is directed at Dr. Josephine Briggs and NCCIH. Whatever my problems with NCCIH, I always thought that Dr. Briggs was trying to steer it towards more scientific accountability, even though by its very nature NCCIH can’t ever truly be scientific. NCCIH’s funding of TACT is a large step backward in terms of making NCCIH less pseudoscientific. In fact, it’s a big step back towards the “bad old days” when NCCIH (then NCCAM) funded studies of reiki distant healing and homeopathy. Apparently the interest in promoting scientific rigor proclaimed in the last two NCCIH strategic plans (or, as I put it, “let’s do some real science for a change”) couldn’t withstand the buzzsaw of quackery demanded by NCCIH’s stakeholders, such as ACAM.

oracknows Thu, 09/29/2016 - 00:30

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Effect Of Heating On Vitamin C Content Of Some Selected Vegetables
Thermal stability of L-ascorbic acid and ascorbic acid oxidase in broccoli

I thought quacks said simple lifestyle changes that they alone can get you to do were all that's needed for heart disease. Why do quacks keep rolling out this Edsel?

Almost $80 million to study a chemical beloved by quacks. It is really odd how quacks like this one chemical so much. I guess its association with quackery around vaccines has made this a good synthetic chemical so therefore it can be used to treat all kinds of diseases in the quack world.

The mindset that if a chemical is good to "treat" vaccine injured kids, therefore that chemical can be used to treat various other diseases seems rather primitive or magical. In contrast, I would assume that a chemical specific enough to treat one disease is highly unlikely to be the treatment for other diseases.

Statistician says: "at worse it adds significant bias" - I don't see how, cause I'm presuming that randomization to the arms will be balanced within each center.

That's a big assumption for TACT. Also, try reading some of Dr. Donnell's magical mystery tour of TACT sites and his post about how blinding was probably compromised at a lot of them. That's actually only a small piece of what was wrong with dozens of sites signing up TACT patients. I could easily have doubled or tripled the length of this post detailing the other—shall we say?—oddities in how patients were signed up and the trial run at many of these sites.

@ Mike

I would assume that a chemical specific enough to treat one disease is highly unlikely to be the treatment for other diseases.

There are notable exceptions, so I'm not sure about this. Aspirin has plenty of applications, and in a recent post here at RI I learned that a number of anti-cancer drugs are used - with some level of success - to treat lupus.

But I would admit that in these cases the different susceptible illnesses share some common modality, so this explains that. You are using your hammer because there is really a nail here.

I think the real assumption to be challenged here, in the first place, is the usefulness of chelation therapy on autism.

I agree that if blinding is compromised, bias can result.
Here's the best article I've read about that (even though it's by a doctor):
http://jama.jamanetwork.com/article.aspx?articleid=1672219

$80 Million, in an age where legitimate research is starved of funds....got to love it.

And where are the IRBs that are supposed to derail unethical studies involving human subjects?

I've never applied for funding on a project that was subject to IRB approval, but my recollection from the internal forms is that, at least at my institution, a prospective PI or institutional PI is required to apply to the IRB before submitting the proposal. In some cases a proposal can be submitted while IRB approval is still pending, but if you haven't applied for IRB approval on a project that requires it, our sponsored projects office will not let your proposal out the door. Admittedly, we don't have a medical school on this campus. How does this policy compare to other institutions: stricter, looser, or comparable?

And yes, where is Sen. Proxmire when we need him? Bad enough to spend $30M on a dubious study that produces null results, when at least such a study hasn't been done before. To spend an additional $37M on a follow-up study to which we already know the answer? That's 20-ish R01s on plausible topics that didn't get funded. Maybe some of even most of those would have turned out to be dead ends, but even so that's a better return on scientific investment than this turkey.

No-one could have anticipated that trying to placate a pack of skeezy grifters by paying them off would simply encourage them to come back and grift some more.

While it does have to do with the brain, many drugs to prevent migraines are anti-seizure or anti-depressants medications used at lower doses.

And of course, the big (heh, heh) example of this is Viagra.

And where are the IRBs that are supposed to derail unethical studies involving human subjects

Actually, apparently there were some IRB shenanigans associated with TACT as well, but I don't know enough of the details and the sources to write about them authoritatively. So I left out that part.

And yes, where is Sen. Proxmire when we need him?

As I recall, the most notable thing to emerge from the "Golden Fleece" awards was Hutchinson v. Proxmire, 443 U.S. 111 (1979).

Thank you NIH for funding another worthless study. Removing the calcium seems pointless, but maybe that is the point: keep the scientists busy doing something that is bound to fail; delay the cure from being known for as long as possible.

CVD can be reversed with diet, and probably has something to do with Vitamin C.

Does anyone want to hear Dr. Linus Pauling's take on CVD? If you do, look no further than this!: A Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality

CVD can be reversed with diet, and probably has something to do with Vitamin C.

Does anyone want to hear Dr. Linus Pauling's take on CVD? If you do, look no further than this!!!: A Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality

And you were doing so well until you got into the vitamin C woo.

And you were doing so well until you got into the vitamin C woo.

It was obvious from the get-go.

@Eric Lund - I've been part of a team that went through the IRB process twice, for epi projects at a local university's school of nursing. They put our proposasl under a microscope -- it was quite a process getting all of our ducks in a row for approval.

And this was for one-page surveys on vaccine uptake in a rural county.

I don't know much about ACAM and chelation. However, one nice, spry old friend in his 80's, a retired judge whose spouse stroked out on Vioxx, swears by it - feels much better and some other claims I need to ask again to quote. Being a lawyer, science was not the major component of his education. Just another favorable testimonial by a person not stupid or insane...

Realizing that some of the adverse history concerns disodium EDTA content (vs tetrasodium EDTA or some degree of protonation in between), I would probably be a little paranoid about precise formulation and experience of a practitioner. Ditto magnesium and vitamin sources, many flavors are possible and could be very important in some cases. I myself wonder about stray heavy metal depletion effects and also cations above divalents.

Personally, I think a thorough phase IV type longitudinal study might be most productive at this point, if each patient could be tagged with their precise particular Formulation and tracked. Even a fraction of patients from 1-2 years of reported treatment would be a vast set of data that could be capped with SSDI results in 5-10 years, a least amongst the older retirees.

True or not, the Pauling theory of CVD does make sense. Linus Pauling didn't get a PhD in Woo!

Linus Pauling didn’t get a PhD in Woo!

Didn't get one in biology either.

True or not, the Pauling theory of CVD does make sense

Plausibility only trumps accuracy in fields such as politics, car-dealing and trolling. I am sufficiently old-fashioned to prefer Truth over Truthiness.

So, are they still claiming the same mechanism of action (removing calcium)? Or are they just throwing patients at the wall to see who sticks?
I'm pretty sure that's not science.

@prn #18: So we're supposed to be impressed by a "my friend" anecdote by someone who's not in the medical field relayed by someone else not in the medical field?

Feeling different is not the same thing as getting better.

A phase IV study would be done only after the treatment is approved by the FDA. It is preposterous to think about studying patients getting this as part of routine care when we haven't even proved the treatment does anything, and when in fact the study that's been done shows that it doesn't work.

Did the Herr Doktor read the paper?

This is the best theory for CVD that I have come across. Does anyone here have a better theory?

Do go away, Fucklesworth.

You're the one admitting that it makes no difference to you whether Pauling's theory is "true or not".

The Pauling theory is like a metatheory that explains why high Lp(a) and salt intake are both risk factors for CVD.
•The higher the blood pressure the more damage.
•The higher the Lp(a), the more plaque deposition
•The lower the Vitamin C, the lower the collagen, and the more sensitive the arteries are to damage.

Can one person take enough Vitamin C to mitigate a lifetime of McDonalds eating and stress? I don't know, but I think that it would delay the inevitable by a few years at least.

Perhaps for all you omnivores out there, you should try to eat one orange for every hotdog.

Blimey! The chelation as therapy believers want to keep researching until their biases are confirmed, looks like.
That's not how it works (I know, preaching to the choir).
And the IRBs are just as delusioned.
What a monumental waste of money, and there is not an insignificant risk to participants I would think.

My Aunt, (who loved every conspiracy theory she could find and was a proud John Bircher) had chelation therapy to prevent heart disease. I have no idea if it did, I just know that by the time she died her arthritis was so severe she had to wear a custom made plastic exoskeleton in order to sit or stand, and suffered from dementia--probably Alzheimer's.
Heart disease sounds preferably to me.

<a href="https://clinicaltrials.gov/ct2/show/NCT02733185?term=tact2&rank=1Looks like it is up on CT.gov.

Why are they randomizing to vitamins again when that was stone cold negative the first time?

Panacea@23
...So we’re supposed to be impressed by a “my friend” anecdote
Actually P, I was citing it as my lack of experience and insight, including not knowing what kind of formula he got. Along with my general disinclination toward disodium EDTA based formulas as likely problematic.

A phase IV study would be done only after the treatment is approved by the FDA. It is preposterous to think about studying patients getting this as part of routine care when we haven’t even proved the treatment does anything
I said a phase 4 type of study. Say what you will, the stuff is in commercial use.

...when in fact the study that’s been done shows that it doesn’t work.
Generally, I believe that MSM trials related to CAM show how not to use materials. I totally believe that if some idiot does it the way a failed trial did it, they can expect to fail too. Typically negative trials on the CAM items I'm interested in have been designed wrong several ways - with no possibility of success to someone who already knows what has worked historically.

Pretty much I can read trials for myself, often figure out what was biased, what was wrong, and adjust or add the parameters, or just discard accordingly. It has become a real survival skill these last dozen years or so. Fortunately I had some similar industrial experience IRL with detecting more subtle commercial biases done for monetary gain.

Lest you think I'm all negative on negative trials, let me assure that I am dependent on some of them to dodge bullets, like on little published but significant drug interactions. Some times I've gone for months looking for a suspected negative.

Generally, I believe that MSM trials related to CAM show how not to use materials. I totally believe that if some idiot does it the way a failed trial did it, they can expect to fail too. Typically negative trials on the CAM items I’m interested in have been designed wrong several ways – with no possibility of success to someone who already knows what has worked historically.

Lest you think I'm all negative on negative trials, let me assure that I am dependent on some of them to dodge bullets, like on little known on interactions. Some times I've waited months looking for a suspected negative.

@prn #31: well you definately succeeded in relating your lack of knowledge on the subject.

There is no such thing as a phase IV "type" of study. There are Phase IV clinical trials, which study the use of a medication in the general population after it is approved, and there different types of quantitative and qualitative research.

The population who gets chelation therapy is small, because treatment for heavy metal poisoning that is actually done for real heavy metal poisoning (ie not quackery) is a small and limited population. They don't get this therapy for anything else, and it's not a routine therapy. Once the heavy metal poisoning is treated that's it. So trying to study this population for the supposed benefits on CVD is simply preposterous. In any event, Phase IV trials study side effects and safety. To gain approval for a new clinical indication, you have to do a whole new Phase III trial.

The only reason the drug companies bother with that is to keep a drug under patent. Off label use is pretty common once other evidence shows a drug can be used for other things. Which is why quacks can use chelation in the first place; they're basically using it off label.

The rest of your post is pure nonsense.

Szilard:

Perhaps for all you omnivores out there, you should try to eat one orange for every hotdog.

Eating more fruit and veg in general is a good objective for most of us, for so many reasons. But that said . . . there actually is vitamin C in meat. Mostly because, unlike humans, most animals can synthesize it. A return to more "traditional" sausages might help increase vitamin C consumption. Organ meats have a lot more vitamin C than mere skeletal meat has. ;-) Maybe if we weren't so picky, we'd have a better diet, and each cow would go further.

Panacea,
What we have here is a failure to communicate.

...which study the use of a medication in the general population after it is... [marketed]
That's the type part, @#$w^&.

EDTA is of course capable of moving and removing metals, especially polyvalents, in lower than immediately, clinically symptomatic amounts.

In real research, Panacea, people sometimes actually go looking for things that are not already known or well understood. Preferably with better tools and minds.

@prn: No, in real research, people form a hypothesis, develop a testable prediction, gather data, and refine, alter, or reject the hypothesis. We don't go fishing in stock pond hoping to find a fish other than what was stocked.

This isn't about what EDTA can move or remove. It isn't even about whether or not the assertion that it can affect CVD is true or not.

It's about ethics, and use of human beings as experimental subjects. What you want to do is completely unethical and puts patients at risk so you can go on a fishing expedition.

We don’t go fishing in stock pond hoping to find a fish other than what was stocked.

Nor do we go fishing in the ocean with no clear idea what we might catch. Fishing expeditions tend to fare poorly in proposal panel reviews, for good reason.

We know that EDTA can remove various metals from the body, some of which are toxic and others even essential. For somebody with a serious case of heavy metal poisoning, it's worth while, because the benefits of removing the heavy metals outweigh the risks that more beneficial metals will also be removed. So these patients get EDTA treatments.

What TACT did, and TACT2 proposes to do, is give EDTA treatments to people who are not known to be suffering from heavy metal poisoning, in hopes that their condition might improve. There doesn't seem to be a rationale behind this other than the standard toxins gambit of woo-pushers, and there doesn't seem to be a physiologically plausible mechanism. On the contrary, there is a demonstrable risk to the treatment, as noted in TACT by the fact that many subjects had to be dropped due to adverse outcomes. The original TACT investigators could at least make feeble arguments from ignorance about the ethical situation (not that these arguments are persuasive, but at least they exist). The TACT2 investigators have no such excuse.

Orac mentioned above that the relevant IRBs for TACT seem to have been either asleep at the switch or subverted. I'll repeat my question upthread: Where are the IRBs that should be derailing TACT2?

Re: Numerous comments about Linus Pauling. I saw him on TV, a live interview/call-in show, taking about vitamin C and the common cold.. He was ,asked about vitamin C and AIDS. He said, "Well it's proved effective against viruses and AIDS is a virus so it should work." I think he was senile.

@Calli Arcale
True, but Vitamin C is a heat-labile vitamin and not many people eat raw hotdogs.

Who makes your favorite brand of broccoli hot dogs, Lewis?

broccoli hot dogs

Border broccollies.

Linus Pauling is one of the greatest chemists ever. Doesn't ORAC have a chemistry degree?

ORAC, who is you favourite chemist? You can't name yourself.

A return to more “traditional” sausages might help increase vitamin C consumption.

That's what the fries and ketchup are for.

ORAC, who is you favourite chemist?

Not ORAC, but I've always had a soft spot for Antoine Lavoisier. Why you ask?

Not ORAC, but I’ve always had a soft spot for Antoine Lavoisier.

Ah, "Ms. Rogers," a new sock. I won't bother with the perfunctory Timmeh answer, although it's not bad.

Linus Pauling is one of the greatest chemists ever

Who is only mentioned on this thread because a sock-puppetting numptie keeps popping up with new nyms to whinge about his limited list of obsessions.

Personally, I was rather fond of Isaac Asimov. At least he distinguished between fact and fiction.

The director of NCCAM discovers Bayesian probability. Hilarity ensues.

oracknows — Thu, 15 May 2014 05:00:28 +0000

The director of NCCAM discovers Bayesian probability. Hilarity ensues.

Over the years, the criticism of "evidence-based medicine" (EBM) that I have repeated here and that I and others have repeated at my not-so-super-secret other blog is that its levels of evidence relegate basic science considerations to the lowest level evidence and elevate randomized clinical trial evidence to the highest rung, in essence fetishizing it above all, a form of thinking that I like to call methodolatry. Now, when EBM works correctly, this is not an entirely unreasonable way to look at things. After all, we just want to know what works in patients. Basically, when EBM is working properly, its underlying assumption is that treatments don't reach the level of double-blind randomized clinical trials (RCTs) without having first gone through several steps first, beginning with basic science considerations, progressing to early stage clinical trials, and then finally reaching the stage of large RCTs. In other words, preclinical studies (basic biochemistry and animal studies) produce biological plausibility that justifies testing a new drug or treatment in clinical trials.

Another important point is that basic science alone can't demonstrate efficacy. However, it can show that a proposed treatment is so implausible based on its purported mechanism of action as to be utterly not worth testing in RCTs, particularly given that clinical equipoise is essential in clinical trials. Think of it this way. For homeopathy to be a valid treatment, our understanding of physics and chemistry would have to be not just wrong, but spectacularly wrong. While it is theoretically possible for scientists to be so wrong about such fundamental physical laws and theories, what's more likely, that scientists are so completely wrong about laws and theories that rest upon a very solid evidence base or that homeopathy is bunk? The same thing can be said of mystical modalities like "energy healing." For example, no one has ever demonstrated the existence of this "life energy" that is redirected to heal or the "universal source" that supposedly provides the energy that reiki masters claim to be able to use to heal. In a nutshell, basic science can tell us that it is, for all practical intents and purposes, impossible that a treatment can work. Basically, it can tell us a treatment doesn't work or can't work, but it can't by itself tell us if a treatment works. Thus has the phenomenon of quackademic medicine entered medical academia through the blind spot in EBM, namely its assumption that a treatment won't reach the stage of RCTs without first having "proven its plausibility" through preclinical basic science investigation. In a sense, EBM was blindsided by "complementary and alternative medicine" (CAM), which is why I've supported the concept of science-based medicine (SBM), which takes into account prior plausibility of proposed treatments.

So it was that I took a lot of interest in an article by a woman who is the director of a not infrequent topic of this blog, namely the misbegotten NIH center known as the National Center for Complementary and Alternative Medicine (NCCAM), a branch of the NIH that studies magic. Ever since I first became aware of its existence, I've kept an eye on the NCCAM researchblog, where Josephine Briggs, MD, the director of NCCAM, occasionally posts. This time around Dr. Briggs tackles the plausibility issue head-on and comes out of it worse for the wear, so poor are her arguments in a post entitled Bayes’ Rule and Being Ready To Change Our Minds. Regular readers might remember that, basically, applying Bayesian analysis to an RCT involves assigning a prior probability that a clinical trial is likely to be positive and using that estimate to weight the statistics. Basically, the lower the prior probability, the less likely that a "positive" trial (with the classic p-value less than 0.05) is to represent a "true" positive.

Where Bayesian considerations are most useful in the discussion of CAM is for modalities that have very low prior probabilities, particularly those that are about as close to zero as you can imagine, like homeopathy, reiki, acupuncture, and the like. If you take Bayes' rule into account, the "positive" RCTs touted by CAM practitioners and quackademics are almost certainly not "true positives." Rather, they're false positives, noise. It's also important to point out that we're not arguing over whether a treatment with an estimated prior probability of, say, 10% is too "improbable" to be worth testing. It probably isn't. What we're talking about is something like homeopathy, whose pre-trial probability, based on the sheer scientific nonsensicalness of its purported mechanism is so close to be zero as to be, for all intents and purposes, indistinguishable from zero.

This brings us back to Dr. Briggs, who's flogging a study that has also been a fairly frequent topic of this blog over the years, namely the Trial To Assess Chelation Therapy (TACT) trial, a trial that tested chelation therapy, a common quack therapy used by naturopaths and others to treat cardiovascular disease, for its effects on cardiovascular complications and death. For the gory details of why this $30 million boondoggle was a complete waste of taxpayer money that endangered patients testing a treatment with close to zero prior plausibility, you can go back and read Kimball Atwood's criticism of the trial design itself and my discussions of the completely underwhelming results here, here, here, and here. (If you doubt me, you really should check out Dr. R. W. Donnell's Magical Mystery Tour of NCCAM Chelation Study Sites, Part 1, Part 2, Part 3, Part 4, Part 5, Part 6, and Part 7, asking yourself if you would trust any data coming from such sites. As Dr. Donnell points out, only 12 of the 110 TACT study sites were academic medical centers. Many of the study sites were highly dubious clinics touting highly dubious therapies, including heavy metal analysis for chronic fatigue, intravenous infusions of vitamins and minerals (I could never figure out how infusing minerals could be reconciled with chelation therapy to remove minerals, but that’s just me), anti-aging therapies, assessment of hormone status by saliva testing, and much more. Dr. Donnell also points out that the blinding of the study groups to local investigators was likely to have been faulty. So right off the bat, this study was dubious for so many reasons, not the least of which was that some of its site investigators were felons, a problem blithely dismissed by the NIH as being in essence irrelevant to whether the study could be done safely.

For those who aren't inclined to click on a bunch of links and read fairly lengthy deconstructions, there were many problems with the design of the study, and the study turned out to be basically a negative study, with no decrease in a composite outcome of aggregated cardiovascular events in nondiabetics and a questionable (at best) claimed improvement found by pre-specified subgroup analysis in cardiovascular outcomes only in diabetics. As I've pointed out before, if CAM practitioners consider this study valid, they would have stopped using chelation therapy for cardiovascular disease in nondiabetics right away. They didn't, and the results in diabetics were not persuasive for a number of reasons.

So what does Dr. Briggs have to say about this trial?

She begins by contrasting TACT to what usually happens, namely that treatments expected to be useful often fail to show evidence of efficacy in clinical trials, saying that every once in a while "the opposite happens." Her lead-in to TACT thus established, she cites the most recent publication based on TACT. There have already been multiple publications, a clear example of what I like to call publishing the MPU (minimal publishable unit), and this looks like yet another reanalysis of the very same data coming to the same conclusion. Seriously, this is touted as a "factorial analysis," but it's the same vinegary wine in a different bottle, which is why I don't plan on doing a particularly deep analysis of the paper. Despite the authors touting the results as showing a benefit in the entire TACT experimental population (which sure sounds to me like post hoc analysis compared to the first primary analysis published in JAMA), the authors simply repeat the claim that the results are especially compelling in diabetics. I've looked at these before before for the previous MPUs from TACT. Suffice to say that there were no statistically significant differences in all-cause mortality, MI, stroke, or hospitalization for angina. There was a statistically significant difference in coronary revascularization, but what that means is uncertain, particularly given that if there was any failure of blinding patients in the treatment group might be less likely to be referred for mild symptoms. Only for the same composite endpoint, a mixture of a "hard" endpoint like death and much "softer" endpoints subject to judgment calls, such as hospitalization and coronary revascularization, showed statistically significant differences. Be that as it may, Dr. Briggs seems inordinately and unjustifiably impressed by the results:

The authors found that those receiving the active treatment clearly fared better than those receiving placebo. The accompanying editorial in the AHJ reminds readers about the value of equipoise and the need to “test our beliefs against evidence.”3

Most physicians did not expect benefit from chelation treatment for cardiovascular disease. I readily admit, initially, I also did not expect we would find evidence that these treatments reduce heart attack, strokes, or death. So, the evidence of benefit coming from analyses of the TACT trial has been a surprise to many of us. The subgroup analyses are suggesting sizable benefit for diabetic patients—and also, importantly, no benefit for the non-diabetic patient. Clearly subgroup analyses, even if prespecified, do not give us the final answer. But it is also clear that more research is needed to test these important findings.

No. It. Is. Not.

Dr. Steven Nissen explained why in an editorial that accompanied one of the first MPUs published from TACT. I've explained why ad nauseam in the links I've included above. This was, in essence, a negative trial. Indeed, its results were as both Kimball Atwood and I predicted: Negative overall but with one subgroup with a suggestion of benefit that lets the authors claim that "more research is needed," which is the same thing that Dr. Briggs is saying. She has to, given that TACT began at NCCAM (albeit before her tenure began) before being taken over by NHLBI. Of course, let's say that, against all reason, you take TACT and its findings at face value. Remember that the trial took $30 million and a decade to do. Are the TACT findings reported by Gervasio Lamas and colleagues, even if completely reliable, compelling enough to justify spending a similar amount of money to follow up. Even considering that if a future study is limited to just diabetic patients and could thus be smaller, we're still talking several million precious research dollars, minimum, to do the followup study, probably at least $10 million or more. Do the findings of TACT justify such an expenditure. I argue that they most definitely do not. It would be, at best, investing a lot of money to study a question that is simply not that compelling and not that likely to help very many people (under the most charitable interpretation of the results) and, at worst, throwing good money after bad, endangering more patients in the process and thus destroying equipoise.

Dr. Briggs then makes an argument that, while seeming persuasive on the surface, is actually less so if you look at it closely:

And TACT findings are indeed a reminder of the importance of retaining equipoise, seeking further research aimed at replicating the findings, and neither accepting nor rejecting findings based on personal biases. The scientific process is designed to weed out our preconceived notions and replace them with evidence.

Note the not-so-subtle implication that critics of TACT are rejecting its findings based not on their amazing unimpressiveness, coupled with the very low prior plausibility, but rather because of "personal biases" and how the scientific method (as represented by TACT, naturally) will weed out those "preconceived notions" and replace them with evidence. Dr. Briggs is very obviously trying to paint critics of TACT as unscientific zealots with an ax to grind. To do this, she cleverly tries to reclaim Bayes for herself, knowing that Bayes is a frequent argument against not just TACT and chelation therapy for heart disease but against CAM itself:

Bayesian methods are getting a lot of attention in the clinical research literature these days. The Bayes rule involves estimating the probability of a result—the prior—then modifying it with each round of new evidence. Another editorialist, a statistician, examined the TACT results, using a Bayesian approach, and comments: “If we start from a position of skepticism, the results of the TACT trial reduces the degree of skepticism. This is exactly how Bayes analysis helps modify prior beliefs by incorporating new evidence and upgrading knowledge.”4

One paper that Briggs cites echoes the sentiment:

When evidence conflicts with expectations, the findings are typically discounted. This response is rational from a Bayesian perspective—if the pretest probability (read “pretrial beliefs”) is low, a positive test (trial) should revise the posttest probability upward, but the result is not conclusive. Scientific paradigms shift only after the weight of evidence builds up sufficiently to move from hypothesis to proven fact. There are some classic examples of clinical trials that overturned conventional wisdom. Postmenopausal estrogen therapy was believed to prevent coronary disease events based on observational studies, but randomized clinical trials showed harm rather than benefit.8 and 9 Antiarrhythmic drug therapy suppresses ventricular ectopy after MI and was therefore widely believed to reduce the risk of sudden cardiac death, but a randomized controlled trial showed that it did not.10 β-Blockers were contraindicated in heart failure until randomized controlled trials proved they were indicated.11, 12 and 13 There are many examples of interventions commonly used—or not used—in practice that failed to show the expected result when tested in carefully conducted randomized controlled trials. In the case of TACT, the intervention (chelation therapy) is not commonly used in practice and most physicians expected the trial to show no benefit, yet a benefit was seen. Either way, we should not let our biases blind us to the possibility that unexpected results might provide an important clue for a new approach.

It is critical to use the scientific method to test our beliefs against the evidence. Simply dismissing results that we did not expect would ignore opportunities to expand knowledge and the armamentarium of effective therapies. This latest report is a useful extension of the previously published work from TACT and should prompt new research to replicate the initial provocative findings and base decisions about chelation on strong scientific evidence, not on beliefs, either pro or con.

Um, no. Not quite. Yes, the results of a prior trial can modify Bayesian considerations for a future trial, but in reality the most parsimonious interpretation of the results of TACT is that chelation therapy for cardiovascular disease does not work. There was basically no effect on mortality, no effect on myocardial infarction, no effect on stroke, no effect on any individual cardiovascular outcome, and only a relatively marginal effect observed in diabetics that could well be spurious. This is thin gruel to put up against all the basic science that fails to find a plausible mechanism for chelation therapy in cardiovascular disease. Basically, Briggs is using a variant of the "science was wrong before" argument, while the authors of the editorial that she cites, David J. Maron and Mark A. Hlatky, mistakenly accept the TACT trial at face value, ignoring its inherent flaws and focusing on Bayes like a laser beam to dismiss TACT critics as hopelessly biased and so hostile to the thought of chelation therapy that we are upset by the results of the study. Believe me, I'm not particularly upset by the results of the study. Equivocal results that show up in only one subgroup or require some factorial prestidigitation to be demonstrated are exactly what critics of TACT predicted given the trial design and the problems in its implementation.

I often think: What would it take for me to believe that, for example, homeopathy works—or at least to start changing my mind? Given its incredible scientific implausibility, to me it would take an utterly undeniable result, such as cures of several patients with stage IV pancreatic cancer. Chelation therapy isn't quite as implausible as homeopathy, because chelation, at least, doesn't involve magic and the memory of water. It is, however, pretty damned implausible. The pharmacology doesn't work. The mechanism is not remotely plausible. It's basically a load of fetid dingo's kidneys. So while Dr. Briggs is correct, as far as she goes, that a surprising result in a clinical trial can modify the plausibility calculations for further clinical trials, TACT just isn't particularly persuasive that we should do so. To illustrate, let me just ask a single question: Should we add chelation therapy to the armamentarium of treatments used in cardiovascular disease, based on this study? Even Dr. Lamas doesn't think this study is enough, nor does Dr. Briggs. Ask yourself this, also: Then should we do another trial costing many millions of dollars to nail down this result? The answer is obvious: No. There are lots of other pressing questions to study for which the funds could be better used.

Proponents of TACT or those who don't know much about chelation who were surprised by the results of the study like to paint themselves as being open-minded and following "true science" while we nasty critics are portrayed as hopelessly biased and close-minded. In reality, proponents of TACT are being so open-minded that their brains have fallen out.

oracknows Thu, 05/15/2014 - 01:00

Tags

National Center for Complementary and Alternative Medicine

cardiovascular diseaes

Josephine Briggs

Categories

Physical Sciences

Do turkeys vote for Christmas?
Dr. Briggs and the NCCAM share the turkey's predicament.
NCCAM have been testing CAM treatments long enough now to have sufficiently proven sceptics to be correct in their negative expectations of success when scientifically nonsensical - but popular - treatments are subjected to careful empirical scrutiny. At what point does NCCAM get wound up and we cease spending tax revenues testing dumb-ass treatments for which there is no reason whatsoever to suppose could out-perform placebo? At best.
Briggs's attempted resurrection of chelation therapy smacks of the turkey's fear of Christmas. We will keep testing our dead turkeys; one of them must eventually be found to be living. The fat turkey that is NCCAM no doubt wants to live forever too.

"The Camptown ladies sing this song
Doo-dah, doo-dah,
I bet my money on a bob-tailed nag
Somebody bet on the Bayes"

Doo-dah, indeed.

It was great to attend the Science and Engineering Festival in DC a few weeks ago. Other than the questionable Avon booth, there appeared to be only one booth that promoted pseudoscience: the NCCAM booth, which featured a vapid (and not engaging) "herb search" for the kids.

Here's a smaller version The version I received had more of these herbs.

I'm sure that Dr. Briggs is trying to justify the continued existence of her little empire. However, she needs to be reminded of the First Rule of Holes: If you're in one, stop digging. Instead, she's asking for a bigger shovel.

OB XKCD: http://xkcd.com/1132/

Really? She's citing Bayesian statistics, for CAM?

Prior plausibility is LOW. Far less than 1%. You check multiple measures, one comes up positive. Frequentist methods say, "There might be something there." Bayesian methods say, "OK, the probability that this works has just ticked up a tiny bit. Still less than 1%."

I'm about as impressed with her use of Bayesian statistics as I am with the average non-physicist's use of "quantum."

"Quantum" has to do with the fact that energy comes in discrete packets, it does not mean that you can do magic. Bayesian statistics says that a collection of negative evidences makes one piece of positive evidence weaker, not that a single piece of positive evidence throws out a collection of negative evidence.

I've brought up the appropriate application of Bayesian analysis in the process of validating Natural/ALT/CAM/Integrative modalities in many of the altie forums I frequent and irritate. It usualy generates a blank response!

And wasn't there some talk back when this study first hit, that the slight apparent benefit for diabetics could be potentially explained by sugar pill placebos making things worse? In other words, that the treatment's only apparent success was that it only did nothing?

I think NCCAM's objections have little to do with science and much more, if not all, to do with full employment: logically, if they rule out a form of alternative medicine (which, it seems, they haven't despite 20 years of research) then some staff would have to be laid off or some studies cancelled, leading to lower funding.

@Gary9
The entire enterprise is a sham. Those who do the testing are almost entirely practitioners of that which they are testing. They are true believers before they even plan their study. If they do perform a HQ study they don't get a positive result. Do they then say, hey I've just discovered that what I've believed for ever is mistaken, that's the end of that then.
No they do not. They wring their study dry squeezing out some fatuous conclusion and sign off with "more research is needed". And so the practitioners carry on practising and testing their treatments year after year. And NCCAM carry on finding ways to avoid saying what a bloody load of nonsense CAM has been proven to be. US tax payers are being taken for a merry old ride.

The director of NCCAM discovers Bayesian probability.

...and NCCAM stops issuing grants.

No, wait, sorry, I confused 'discovers' with 'understands'.

I'm going to make a slightly contrarian case here.

Bayesian priors appear to be an exercise in positing subjective value judgements as ratio-scale variables. That's a big no-no, quite like trying to rate 'love' or 'loyalty' or whatever on a scale of 0 to 100. 'How do I love thee? Let me count the ways,' makes for touching Victorian poetry but does not translate to an objective measurement.

And worst of all, it isn't even necessary, so it muddies the waters and gives quacks & their enablers an escape hatch of arguing over Bayes numbers.

Given a data set from a faith healing experiment, shall we argue whether it should be interpreted with an atheistic prior of 0, or a faith-based prior of 1, or perhaps an agnostic prior of 0.5? The atheist will find much favour from scientists but have no credibility with the religious public, thereby creating a backlash in support of faith healing. The theist's situation is reversed but the religious public will take it as affirmation and demand laying on of hands in hospital. The agnostic is on solid ground empirically (since the existence of deities is not testable) but none the less will be criticised by the atheists and the religious public alike. Either way, the arguement will continue until the proverbial cows come home.

The only people to benefit from that, are the likes of Mercola and the Wizard named Oz.

Falsification of quackery should be entirely possible with frequentist methods, leaving nothing to be argued except possibly the details of methodology, that themselves should be purely objective (e.g. quantity of compound administered, reduction in measurable objective signs of illness, etc.).

Here we have a study of TACT that demonstrates insignificant results on most measures, and a slightly significant result in one area. If we apply a low prior to make the latter disappear, we only end up creating ground for arguement.

Or we can show that the significant outcome is irrelevant because other treatments that are well supported have much more significant outcomes. Why, after all, should anyone in their right mind seek out a treatment modality with questionable efficacy that is at best low, when there are other treatments with reliable empirical support and much higher efficacy?

The fact that Bayesian methods work for certain applications such as the maths used in cryptology, does not make them universally relevant. The frequentist case for dismissing TACT, and homeoquackery, and 'energy healing,' and the rest of that rubbish, is much stronger.

Jenora have made some important remarks here, I have similar thing in my mind,

Jenora:
And wasn’t there some talk back when this study first hit, that the slight apparent benefit for diabetics could be potentially explained by sugar pill placebos making things worse? In other words, that the treatment’s only apparent success was that it only did nothing?

@Lurker

I'm afraid I must disagree very strongly with you.

First your description of Bayesian priors and their setting is just wrong. It repeats the old
trope that somehow we are being 'subjective' and further more that being 'subjective' implies
'making it up'. Perhaps in the history of Bayesian inference there has been an unfortunate
tendency to use the word 'belief' which has lead to this but really it comes from a 'philosophical' objection
by frequentists which is largely an objection to their own interpretation, which they stick to despite all
evidence that their approach is flawed.

You suggest that we shouldn't use Bayesian inference because it appears to give our 'opponents' opportunity
for misuse and abuse. Indeed it does, but when we are doing science we don't have 'opponents', we seek the truth
with the best possible tools to hand, not the tools we think most likely to 'win an argument' whatever their standing - its a truely bad argument for use of one methodology over an other and would be just as bad if you had been arguing the opposite.

You claim that somehow Bayesian inference isn't universally applicable. Really? Do you seriously believe that we pick and choose our methods to suit our cause and that for some reason this system of inference
(ie the logic of dealing with uncertainity) is applicable to some domains and not others? In what possible way can
you justify this statement? How do you differentiate yourself from, for instance, homeopaths who claim that RCT (and the rest) are not applicable to their particular science. I see no difference.

Indeed, frequentsist statiscs as a 'methodology' stands in some way as homoepathy does to medicince. When confronted with a problem, one consults the 'big book of recipes' and extracts a procedure that received wisdom has said one shoud use.
There is some vague talk that sounds like a rational basis, and after all there are symbols used that look like mathematical symbols. But lift the hood and we find a lack of theory and grounding, and indeed the ability to question'why?'.
Bayesian inference on the other hand, is a true theory of statistical inference, derivable from pellucid and up front assumptions (axioms),
it justifies much of frequentists procedures - a difference of course in the homoepathy analogy being that frequentist stats does often
reach the right conclusion a lot of the time - though it doesn't know why - Bayesian inference puts it on a solid footing.
Of course the frequentists approach is wrong some of the time, and there are issues that its simply can't deal with in any consistent manner.
So, on one hand we have some big books of ad hoccerys which may or may not be justified, on the other we have a rigourous,mathematical approach to logical inference (which is of course universally applicable - sorry but that was just silly!)which condenses, explains and is very successful in practical applications. Take Bertrand Paradox - a paradox for frequentists because their ad hocceries
simply don't differentaite the three possible answers they come out with. No issue for Bayesian analysis.
Rigourous mathematical deduction leads to a unique answer which is both intellectually satisfying, and has also been empirically tested. This tour de force of reasoning coupled with empirical validation not to mention all the other advances Bayesian
inference has made, is usually enough for people to claim an advance in science and drop their old ways, not so in statistics for reasons that often appear
not so different to those touted by quacks and woomeisters.

Of course, Bayesian analysis is basically more difficult, more mathematical and there are acknowledged problems to be resolved - the setting
of priors being top of the list - though symmetry principles, maximum entropy etc appear to be making a start (by the way - where in the
'Well-Posed Problem' do you see any 'subjective' priors?). There is more to say on priors - but plucking numbers out of the air is in no way part of Bayesian methodology.

My friend - no procedure, whatever its provenance, is likely to convince these people out of their barmy beliefs.
Instead of following them by trying to pick and choose and making specious and unfounded declarations about applicability and relevance,
drop the 'intuitive magic' that is frequentist statistics and come into the fold of rigourous scientific analysis that is currently
best represented by Bayesian analysis. Perhaps if we teach the next generation how to think properly about uncertainty they will have
a chance to avoid the new dark age that sometimes when I read this blog and others like it seems imminent.

In which Orac gets even more "shrill and brutish" about chelation therapy and TACT

oracknows — Wed, 10 Apr 2013 02:09:44 +0000

In which Orac gets even more "shrill and brutish" about chelation therapy and TACT

If there's one thing that a certain subset of people who view themselves as reasonable and science-based don't like, it's harshness: Harshness in criticism, harshness in discussion, or—horror of horrors!—anything they view as "incivility." That's all well and good as far as it goes, but the problem is that sometimes there are things that demand a harsh response because they are just that bad. For instance, when the government spends $30 million on a clinical trial to test a wildly implausible treatment that is not without risks for no good scientific reason and no real reason other than that quacks are using it now, then I find that to be a good reason to be harsh, particularly when the therapy used is not without risk.

Apparently, Orac is "shrill and brutish" for saying so in no uncertain terms. At least, so sayeth eminent Yale cardiologist Dr. Harlan Krumholz in a post on his Forbes blog yesterday. Apparently, he was quite offended by my criticism of his unfortunate comments about the results of the Trial To Assess Chelation Therapy (TACT), which were reported in JAMA a couple of weeks ago. Sadly, Dr. Krumholz is quite misguided in his assessment, as I pointed out before. However, his characterization of my original post is not my main concern, although I will address it more towards the end of the post. First, let's deal with what's most important: TACT itself.

What caught my attention more than Dr. Krumholz's concern trolling and castigation of the critics of TACT (and me in particular) for supposedly being so very, very mean and nasty is his discussion of an interview on Cardioexchange in which Gervasio Lamas and the other TACT investigators respond to the copious and, in my not-so-humble opinion, well-deserved criticism of TACT. It is laden with straw men and other logical fallacies, plus unconvincing defenses of the numerous problems with TACT that were so well documented by Atwood et al in 2008. In fact, I find it far more useful to deconstruct the disingenuous and self-serving defense of TACT than to worry overmuch about the concern trolling being flung about by someone like Dr. Krumholz, who from his article (in which he points out that he knows Dr. Lamas and assures us that all the main investigators for TACT are awesome clinical trialists) appears more than anything else to be really ticked off that his good buddies are being criticized. How dare we peons say such mean and nasty things about his good buddy, who, he assures us, is really and truly a total dude? I'll explain why, and I can't think of a better starting point than Dr. Lamas' answers to TACT critics, which is basically a fawning puff piece in which—you guessed it!—Dr. Krumholz himself lobs softball interview questions at Dr. Lamas and company. Sadly, given that the questions Dr. Krumholz served up were more akin to batting practice pitches than anything challenging, you'd have expected that Dr. Lamas could have hit every one of them out of the ballpark. Instead, what we get are at best inconclusive foul balls devoid of illumination and mostly resting on the very same shortcomings of evidence-based medicine as opposed to science-based medicine that I've been discussing for years now.

It turns out that some of the questions are rehashes of issues that I've already discussed in detail before; so I will in essence "cherry pick" the answers that interest me now and refer you to my previous posts about TACT for criticisms of other responses by Dr. Lamas. For instance, the very first question is about statistical significance and how the results of TACT just barely reached statistical significance, the criteria for which were changed based on the enrollment. I discussed that issue in my original post on the presentation of the first results of TACT back in November, and, quite frankly, it wasn't much of an issue for me other than that the ultimate result of the trial was statistically significant only by the barest whisker, with p=0.035 and the predetermined level of statistical significance being 0.036. Indeed, I don't really even care if there was diddling with the statistical significance threshold; I'll even accept Lamas' response at face value. Think of it as a freebie. It changes nothing; it's not even the worst thing about the trial, although I can't resist mentioning again that this barely statistically significant result appears to have been driven entirely by a seemingly beneficial result in two subgroups: diabetics and those with anterior MIs. There were no statistically significant differences between any of the other subgroups. Nada. Zip. To repeat: A proper discussion of the trial would emphasize that. But let's move on, as I've discussed that issue in detail before.

One of the main complaints about TACT was that the endpoint of the study was a composite endpoint that included "soft" outcomes. In other words, instead of looking at the effect of chelation therapy on death, MI, stroke, coronary revascularization, or hospitalization for angine individually, the investigators created an aggregate outcome for "major adverse cardiovascular events" which included all of these outcomes lumped together. Now here's Dr. Lamas' explanation:

The primary endpoint consisted of time to the first occurrence of the following major adverse cardiovascular events: death, MI, stroke, coronary revascularization, or hospitalization for angina. Combined endpoints are used when the most important endpoint to provide proof of efficacy, all-cause mortality, is likely to occur so seldom that an impractical and unaffordable number of patients and patient-years of follow-up would be needed to have enough statistical power to detect a difference between groups. In a stable coronary disease population, the incidence of mortality is low, so a combined primary endpoint is necessary for most studies. As we were planning the study, we selected a population very similar to that of the WIZARD study, which used a primary endpoint similar to ours. Other studies with similar combined endpoints, particularly including revascularization, are JUPITER and ACCELERATE.

Once again, composite endpoints are not in general a good thing. There's but they can be made less bad, so to speak, by not including subjective endpoints like coronary revascularization and hospitalization, both of which are subject to a great deal of clinical judgment in deciding who requires them. More problematic is the variation in usage of such interventions that has nothing to do with whether the treatment works or not. For instance, in the state of Michigan, there is up to a 2.4-fold variation in rates of percutaneous coronary interventions (PCI; i.e., angioplasty) between the highest use and lowest use areas. That's just one state. Similar studies have shown wide variability in coronary revascularization rates just on geography alone. Adding such a variable to a composite endpoint is thus a bad idea on a scientific basis alone. At best, it could add unnecessary variability to the composite outcome measure for no useful benefit; at worse it could add significant bias, particularly if subjects being treated in academic centers, where patients are more likely to be referred for appropriate coronary revascularization interventions were in areas with significantly different PCI usage rates than areas where subjects being treated in "complementary and alternative medicine" (CAM) centers, where one might reasonably expect that referral for revascularization might be a bit less—shall we say?—expeditious. I could see a composite endpoint in which the components were all "harder" endpoints, such as the triple endpoint of death, nonfatal MI, and nonfatal stroke, but even such endpoints are not without problems.

Let's just put it this way. The excuses made for lumping the "hard endpoints" with the more subjective endpoints are just not that convincing. For example, if, as Dr. Sanjay Kaul argues, "the inclusion of subjective endpoints like CV hospitalization and revascularization increases the potential for ascertainment error and misclassification that typically biases the results towards the null," then it was stupid (oh, dear, there I go being "shrill and brutish" again!) of Dr. Lamas to include such subjective endpoints in his composite outcome measure because by doing so he would have decreased the chances of a $30 million trial under heavy fire of producing a positive result and provided opponents of the trial a convenient weapon to use against it, to boot. Whatever I think of Dr. Lamas' decision to take on TACT, I don't think he's stupid. I think he probably thought that using a composite endpoint would decrease the sample size necessary to achieve the desired statistical power, which is the reason some cardiovascular investigators use such composite endpoints.

Oh wait. There's no "probably" about it. That's exactly what Dr. Lamas said in his justification for using the composite endpoint!

Unfortunately, such endpoints are fraught with problems. A sampling of articles describing such problems in detail can be found here, here and here. In fact, if you start typing "problems with composite endpoints" into Google, it will autocomplete with "in cardiovascular studies." To preempt the likely criticism, I am only mentioning this as an indication that there are lots of problems with composite endpoints in cardiovascular trials, to the point where people search for the term a lot. Besides, the articles I referenced more than indicate that such composite endpoints have major problems. Let's just put it this way, a common retort to criticisms of such endpoints is that there have been lots of major cardiovascular trials that used such endpoints. If that's true, then the state of cardiovascular research is not as good from a scientific standpoint as I had previously believed. Indeed, the responses to criticisms of the TACT trial have given me an education in this area, and I don't mean that in a good way.

Another aspect of TACT that we skeptics have always found problematic is the inclusion of heparin and other compounds in the chelation solution but not in the control, which led to this exchange between Dr. Krumholz and the TACT crew:

A major comment concerns the components of the chelation therapy, specifically about the inclusion of procaine and heparin and their possible effects on cardiovascular outcomes. Why were they included, and do you think they had an effect?

The NIH RFA to which we responded had gone through NHLBI and NCCAM Councils and called for a definitive trial of EDTA chelation therapy, as it was currently being implemented in clinical practice. When we looked into the infusions, we found that they included many compounds, not just EDTA. Therefore, to achieve a result that would be consistent with how chelation therapy is actually used in practice, we chose to mimic precisely the most prevalent infusion in use. We have no reason to believe that a small amount of procaine or 2500 U of unfractionated heparin once weekly would affect outcomes to the extent that we found in TACT.

Another comment is that the placebo solution contained 1.2% glucose in order to match the osmolarities of the control and experimental solutions. Some people think that might have contributed to worse outcomes in the control group. What is your view of that possibility? What options did you consider for the placebo infusion?

We wanted to keep the placebo solution as simple as possible and not introduce an unexpected risk or benefit. Normal saline fit the bill, as we excluded patients who had active heart failure. The amount of glucose in 500 mL of 1.2% is 1.2 grams X 5 = 6.0 grams of glucose weekly. It is not plausible that this would lead to a greater coronary risk in diabetic patients. We also considered other iso-osmolar solutions such as D5W but felt these would have introduced a greater sugar load. Another option would have been a solution that encompassed all the ingredients except EDTA. However, as stated above, our intent was to investigate a treatment currently in use and determine whether it was safe and effective, rather than deconstruct the solution. The present design allows us to draw those conclusions.

I'm particularly amused by the statement that they have "no reason to believe" that the heparin or procaine would affect the outcomes. The reason is that Lamas and colleagues really had "no reason to believe" that chelation therapy would have any beneficial effect, but that didn't stop them from spending $30 million of taxpayer money to do this trial and expose hundreds of patients to potential danger for damned near no chance of benefit. There are also other differences, too, that Dr. Lamas doesn't mention, such as magnesium chloride (2 g) and vitamin C (7 g). The placebo solution consisted of 1.2% dextrose in normal saline. Now, the idea is that it's the chelation that matters; yet the study design was incapable of testing whether that was true. Yes, I know that the high dose vitamins and minerals were also tested, but there was really no reason to think that they would be beneficial either, and lots of reason to think that in some patients they might be harmful. In any case, if you're going to test whether chelation therapy does any good, then test whether chelation therapy does any good. TACT was designed in such a way that it can't answer that question.

As for the bit about wanting to test chelation therapy "as it's done in the community," that's one of the lamest excuses I've ever heard. it really is. Think about it. Don't you want to test the idea behind the therapy? Even if I accepted the results of this trial as likely to be valid, I'd be infuriated that the trial was done in such a way that it can't answer the question of whether chelation therapy has any biological validity as a treatment for atherosclerotic cardiovascular disease.

I suppose I'm just being "shrill and brutish" again.

Come to think of it, so is Dr. Lamas:

Much of the criticism and controversy surrounding TACT was originated by several small, self-appointed groups with a history of aggressive opposition to CAM practices and to TACT in particular, as they feel that 1) CAM practices should not be studied; 2) if studied and the results are negative, the trial should be condemned as a waste of money; and 3) if studied and the results are positive, the trial should be condemned as incompetently and unethically carried out, and the results discounted. Obviously, TACT has received the 3rd response. We ask our cardiology colleagues to look at the study critically, without emotion, and ask themselves if they would feel the same way about our results if the words EDTA chelation never appeared, and instead “stem cell” or “new statin” appeared. We believe that the debate should focus on the unexpected biological activity of chelation therapy rather than on spurious allegations that TACT investigators were involved in willful wrongdoing that affected the results of the trial.

To which TACT defender (or at least someone who argues that TACT isn't as bad as all we "shrill" critics say) Dr. Sanjay Kaul adds:

I agree with the notion that there is clearly a double standard when it comes to accepting the results of trials evaluating so-called dubious quack cures such as chelation versus trials assessing promising de rigueur cures such as gene transfer or stem cell therapy.

Actually, to Dr. Lamas, Dr. Krumholz, and Dr. Kaul, I would say: Yes. You might not believe me, but, yes I would feel the same way about the results. In fact, let me throw the question back at Dr. Lamas and Dr. Kaul in a manner relevant to TACT: Would you feel so satisfied with the results of a study of, say, stem cells that produced the same results as TACT? Now, imagine: Would you take such results seriously enough to think that there might be something there and to advocate more study, if you knew that many of the centers where the trial was carried out make their living selling stem cell quack treatments like this one or this one, along with all manner of other quackery, from homeopathy to antiaging quackery, to just about anything you can imagine that's pseudoscientific medicine? You think that's unfair? No, it's not, because that's exactly what many of the "CAM" treatments administered at these centers are like. I refer you back to my description of the quack centers recruited to participate in the clinical trial, as summarized by Dr. R. W. Donnell and his Magical Mystery Tour of NCCAM Chelation Study Sites (part 1, part 2, part 3, part 4, part 5, part 6, part 7). Many of the study sites are highly dubious clinics touting highly dubious therapies, including heavy metal analysis for chronic fatigue, intravenous infusions of vitamins and minerals, antiaging therapies, assessment of hormone status by saliva testing, and many, many more forms of quackery.

If I'm ever feeling particularly shrill, I might go through the entire list of TACT sites and see what other quack therapies many of them offer. Alas, I'm too tired tonight as I write this, and this post is already too long. It would probably take several hours to do.

Recall that Dr. Krumholz characterized my post on the TACT results as "shrill and brutish." Dr. Krumholz proclaims himself to be so very, very offended at the "shrill and brutish" tone of the criticism of TACT, wanting to "steer the public dialogue back to the science," and be a champion of "respectful and civil" dialogue. Excellent! I applaud him on his resolve and hope that he actually goes through with this, but—whoops!—Dr. Krumholz basically said the same thing as Dr. Lamas but in a less "shrill" fashion in his original post on TACT; so I suppose he agrees with Dr. Lamas. He also links approvingly to an interview he did with his good buddy Dr. Lamas in which he accuses TACT critics of, in essence, hypocrisy. Apparently it's just fine to be—dare I say?—shrill and brutish in attacking one's critics, as long as one is a friend. Tribalism? Oh, yes. That's definitely what I'm detecting here.

But let's get back to what Dr. Lamas is saying. Do you detect any straw men here? I detect at least two. Number three is certainly a straw man in that we are not just reflexively dismissing the results of TACT because we think chelation therapy is quackery (although it is). Yet that is exactly what Dr. Lamas is more than implying. Indeed, when his criticism is boiled down to its essence, Dr. Lamas is basically calling TACT critics dishonest and hypocritical. (How "shrill"! Funny how Dr. Krumholz seems not at all "offended" by that.) We are criticizing TACT because we honestly believe that it was bad science and unethical, just as, I expect, Dr. Krumholz honestly believes TACT isn't so bad to the point where he thinks a followup study is mandated.

Number one is also a straw man, indeed a straw man that Dr. Kaul probably doesn't realize is beloved of cranks and quacks of all stripes. None of us say that CAM shouldn't be studied. What we say is that practices that are so implausible as to be incredibly unlikely to yield informative results are not worth doing and potentially unethical. These include treatments whose proposed mechanism violates scientific principles that rest on far more solid evidence than equivocal, bias-and-error-prone clinical trials. These include energy medicine, claims based on nonexistent anatomic structures (such as reflexology, iridology, and chiropractic subluxations), claims that violate multiple laws of physics (for instance, homeopathy) and and claims based on nonexistent physiological functions. Now, it's actually a fairly interesting question (to me, at least) where chelation therapy stands in this order of pseudoscience. Even defenders of Dr. Lamas, such as Dr. Sanjay Kaul, are quick to say that they "do not endorse" chelation therapy for cardiovascular disease. Then they go right ahead and defend the trial.

In fact, Dr. Kaul exhibits one of the key problems with TACT defenders, and that's a misunderstanding of what it is that we are actually saying. For instance, he argues:

First, let me state there are several examples in medicine that have shone the spotlight on the slippery slope argument of plausibility (antioxidant vitamins, hormone replacement therapy, magnesium for MI, anti-reperfusion injury therapy come to mind). Thomas Huxley said it best, “the tragedy of science, the slaying of a beautiful (plausible) hypothesis by ugly facts!”

Ah, yes, it's a variant of the "science was wrong before!" gambit. I know that Dr. Kaul doesn't realize that he's using a favorite argument of cranks and quacks, but he is, unfortunately. As a breast cancer surgeon, I happen to know a bit about hormone replacement therapy, and the problem with HRT was far more that it was adopted prematurely without adequate study. (Rather like chelation therapy by quacks, actually.) It's also a lot more complicated than "hormone replacement therapy was considered good but is really bad." In any case, Dr. Kaul clearly misunderstands plausibility in the way we argue it, because he then goes on to say:

Second, the reason for the low prior probability of benefit assertion is not clear to me. The available evidence for treatment effects of chelation therapy in patients with coronary heart disease or peripheral arterial disease is mixed, and limited to case series and three small trials evaluating surrogate endpoints. No outcome data derived from properly designed clinical trials existed to support or refute treatment effect! Despite the lack of supportive evidence, the number of patients undergoing chelation therapy increased by >50% between 2002 and 2007. Thus, it was important to clarify the benefits and harms of chelation therapy in a controlled outcome trial. Accordingly, the argument that the trial was unethical, as has been suggested by some, doesn’t hold water!

Unfortuantely, Dr. Kaul apparently unknowingly uses the logical fallacy known as argumentum ad populum to argue that the trial is not unethical because, hey, chelationists are out there doing it; so it's ethical to adopt their methods and to study it. The only proper response to that argument, I'm afraid, is not, "If you can't beat 'em, join 'em," but rather to state that chelation therapy should not be given outside the context of a properly constituted randomized clinical trial, and no randomized clinical trial is justified until there is a lot more preclinical evidence to support one. Imagine if a drug company tried to justify a clinical trial for a drug based on the thin gruel of preclinical and clinical studies of chelation that existed before TACT. I'd bet that Dr. Kaul and Dr. Krumholz would be outraged. Yet they don't mind such reasons when they are put forth to justify TACT. In any case, the trial is every bit as unethical as Dr. Atwood and colleagues have argued and Dr. Atwood has reiterated.

It's also more than just the lack of preclinical and clinical evidence, although Kimball Atwood and colleagues laid it all out in excruciating detail in an extensive analysis published in Medscape in 2008 entitled Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned. I strongly suspect that Dr. Kaul has not read the whole thing. It is not that there was no evidence to support or refute chelation. The question was: Did those trials show any convincingly positive signal worth spending $30 million for a huge multicenter clinical trial of a couple of thousand patients to followup on? The answer is no, particularly given the extreme implausibility on a physiological basis, an implausibility in pharmacology that doesn't make sense either in mechanism or, even if one accepts the mechanism might have validity, stoichiometry. (I hope Drs. Krumholz and Kaul, will click on the links and actually read the mechanistic criticisms this time. It's so obvious that they didn't bother last time.)

Dr. Kaul's otherwise well-considered Bayesian argument ultimately fails because he, like so many, almost certainly vastly overestimates the prior plausibility of chelation therapy, estimating a 5% prior probability of an extreme treatment effect (i.e.,>25% risk reduction or >33% risk increase. Many would argue that this is a reasonably skeptical prior distribution, going on to say that "many would argue that this is a reasonably skeptical prior distribution." Perhaps "many" would, but "many" also ignore the lack of even suggestive evidence in human or animal studies and the extreme mechanistic implausibility. 5% is way too high. Maybe 0.05% (or 0.5% if I'm feeling particularly generous). Some would call my estimated prior plausibility far too generous, but I will concede that we're not talking homeopathy-level implausibility (about as close to zero as it's possible to imagine) when it comes to chelation.

Dr. Kaul, like so many good-hearted academic physicians unfamiliar with quacks, seems to imply that there is sort of “societal value” to test interventions that are widely used in society even when those interventions whose proposed mechanisms are highly implausible. I might agree with him up to a point, except for two considerations. First, no amount of studies will convince, for example, homeopaths that homeopathy doesn’t work. Similarly, chelationists are still giving chelation therapy to nondiabetics even though TACT itself is as negative as a negative trial can be on that question: Even by the most optimistic interpretation of TACT, chelation does not work for nondiabetics and those without an anterior MI. Second, research funds are scarce and likely to become even more so over the next few years. From a societal perspective, it’s very hard to justify allocating scarce research dollars to the study of incredibly implausible therapies like chelation therapy for atherosclerotic cardiovascular disease. Given that, for the foreseeable future, research funding will be a zero sum game, it would be incredibly irresponsible to allocate funds to studies like TACT knowing that those are funds that won’t be going to treatment modalities that have a far better chance of actually working. In other words, it's not often a good idea to test highly implausible health claims without more preclinical data that make them less implausible. Such a failure to consider prior probability appropriately has led to truly unethical clinical trials of, for example, homeopathy for infectious diarrhea in children in third world countries.

Finally, there's the issue of wrongdoing among TACT site investigators, something that really, really gets Dr. Lamas' dander up, not to mention Dr. Kaul's as well. This is probably worth a post of its very own, given how complex the issue is, but let me just point to post by Kimball Atwood and a PDF of a newsletter to TACT investigators as a little wafer to cleanse the palate.

Kimball Atwood points out examples of problems. For instance, Dr. Rajiv Chandra of Melbourne, FL, is frequently cited as the “top enroller” for the trial. Chandra, as Atwood et al explained, promised this to prospective subjects:

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.

Ooops! Did he just promise in an ad to provide the study drug? OK, OK, maybe it's a newbie site investigator making a rookie mistake. Maybe. Interestingly, however, there is this newsletter, in which Dr. Lamas apparently feels obligated to warn site investigators against certain actions:

During follow-up phase, after the study infusions, patients must not start open-label chelation therapy at the TACT site or at any other site.
Offering free infusions after the end of the study as an inducement to recruitment is not recommended.
Patients must not receive open-label chelation during their participation in TACT. (5 years after enrollment or in July 2009).

It sure sounds to me as though something was going on at some sites that Dr. Lamas was concerned enough about to warn his investigators not to do. Otherwise, why would he have bothered? One wonders, one does. But that's enough for now. This post is long even by Orac standards, and it's late. Much of the deconstruction would involve delving deeply into various reports and Dr. Lamas' responses. So I'll finish with an observation that comes from what is definitely the most risible statement in an article full of risible statements, Dr. Lamas' response a question about the documented fact that some of the TACT site investigators had been involved in insurance fraud and others were convicted felons:

Were there investigators who had violated the law – and how might unethical behavior by individuals who strongly believed in CAM have altered the trial? Is this any different from other trials where investigators are invested in the success of the intervention – or did this trial have specific issues that must be considered?

All investigators had an unrestricted license to practice medicine in their states, and they received human-subjects training, protocol training in person and online, research training, IRB approval, in-person site visits, and electronic data monitoring by the Data Coordinating Center at Duke.

Yes, that's right. Dr. Lamas completely dodged the question, and Dr. Krumholz let him! In any case, apparently Dr. Lamas' standards are that all site investigators had to have was a medical license and a pulse, as long as they did the training mandated. Never mind those disciplinary actions by state medical boards and insurance fraud! Yes, that's a very low bar indeed for clinical investigators.

I understand that Dr. Krumholz and Dr. Kaul have probably never dealt with quacks who sell chelation therapy and aren't aware of the ins and outs of the history of TACT. (That's why they should read the deconstruction by Kimball and colleagues.) I also realize that Drs. Krumholz and Kaul are buddies with Dr. Lamas. So automatically TACT critics are the outsiders, and I'm "shrill and brutish," and so very, very mean and nasty, for writing all the things that I've written about TACT, which is run by such a good buddy and fine clinical investigator who couldn't possibly have ever gotten himself involved in something so questionable as TACT. So obviously, to them, TACT can't possibly be so dubious and questionable! It just can't be! I understand that. Now understand this: I could be a bit more civil if I wanted to be, but, in reality, seeing $30 million wasted on a pointless and unethical trial of a highly implausible form of quackery that endangers patients with almost no likelihood that they will be helped makes me just a wee bit angry. And when I get angry I guess I get a bit "shrill and brutish." Sometimes, however, it's justified. This is one of those cases.

Obviously, Dr. Krumholz must agree on some level. Certainly he didn't criticize Dr. Lamas for his not-so-subtle labeling of TACT critics as dishonest and hypocrites. I'd take his protestations of wanting a "civil discourse" more seriously if his calls for "civility" weren't so one-sided. He's just too nice to take the next step and express a bit of anger himself when he deems it justified.

oracknows Tue, 04/09/2013 - 22:09

Tags

cardiovascular disease

chelation therapy

Categories

Physical Sciences

This is realy brilliant and devastating for the TACT-people. What are the chances that the money wasted by the NCCAM will be redirected towards usefull research? In my country the governement stopped supporting reseach into alternative medicine in the nineties!!

Hooray for the enlightened Dutch. If only more would follow…

They are asked if there's any evidence of unblinding, and respond by discussing the process they used to blind the samples. Which is, of course, dodging the question.

All investigators ... received human-subjects training, protocol training in person and online, research training, IRB approval, in-person site visits, and electronic data monitoring by the Data Coordinating Center at Duke.

Dodging the question, indeed. You can make your protocol as detailed as you like, get your IRB to approve it, and train your co-investigators in it. That doesn't mean a thing if those co-investigators choose not to follow the protocol. Site visits can help with that, somewhat, if they are unannounced--but if you tell people ahead of time that you are making a site visit on a particular day, they can follow your Potemkin protocol on that day, and ignore it the rest of the time.

It could have been worse. Orac might have been accused of being nasty, brutish and short. Or even a Pharma Shill.

It's early days, though.

DB, you made me laugh!

I am rather shocked at just how badly this trial seems to have gone. I'd say anger is justified. They are not doing themselves any favors by dodging direct questions.

A combo insult would be calling him "shill and brutish".

The "shrill and brutish" thing still boggles the mind. It conjures an image of Truman Capote bulked up from anabolic steroids.

Shrill and Brutish would make a great name for a punk band.

DB: Truman SMASH!

I've only seen Orac via the magick of the internet, but he's certainly neither brutish nor short and I doubt he could be nasty without a great deal of effort.
He appears to be a mild-mannered, white guy.

Although I know a few of those who are quite different when out of a business situation. Believe me, shrill is only the start.

The law firm in Gravity's Rainbow comes to mind -- Salitieri, Poore, Nash, De Brutus and Short.

I love Thomas Pynchon.

Off Topic A Little:

I keep seeing the utterly implausible "THC OIL CURES ALL CANCERS!!!!" crap going around and around on Facebook.

Eventually (okay, I'm sure it's already happened), that's going to get someone killed, in a particularly painful and avoidable way.

Think you could do a post on that one?

Dr. Lamas' response seems to need qualification or correction:
"All investigators had an unrestricted license to practice medicine in their states, "

An "unrestricted" license cannot logically have conditions.

In 2006 this investigator was put on probation with conditions: http://www.circare.org/tact/allen_20060124.pdf

In 2007 this investigator had his license revoked & stayed & he was put on probation for 5 years with terms and conditions:
http://www.circare.org/pd/golden_20071227.pdf

In 2007 this investigator's license was suspended for 180 days followed by reinstatement agreement including probation with terms and conditions
http://www.circare.org/pd/johnson_20071212.pdf

TACT IIRC enrolled the first subject in September 2003 and the last subject in October 2010. The investigators above had variously restricted licenses during TACT.

But licensure status skirts an important issue: there are thousands of qualified cardiologists and experienced trialists in the U.S. so why select physicians with no research experience, physicians with criminal convictions, or physicians with disciplinary actions involving dishonesty?

Herr Doktor @11 and autismum @12 -- Although I studied German, it took me a little while before I figured out the joke in the secretary's name ---

"You're doing FINE, Miss Mueller-Hochleben!"

I keep seeing the utterly implausible “THC OIL CURES ALL CANCERS!!!!” crap going around and around on Facebook.

This is the Rick Simpson crowd. I suppose that if I found myself with a glioma, I'd give it a shot over Burzynski.

#13 there are all sorts of stupid warnings on Facebook--most of them are half-truths designed to frighten people about old cake mix and Mountain Dew, as far as I can tell. It's exhausting trying to keep up with the debunking.

Criticizing the Trial to Asess Chelation Therapy (TACT) is defending science-based medicine

oracknows — Wed, 27 Mar 2013 23:01:15 +0000

Criticizing the Trial to Asess Chelation Therapy (TACT) is defending science-based medicine

When I wrote about the Trial to Assess Chelation Therapy (TACT) trial last week, little did I suspect that I would be revisiting the topic again so soon. For those of you not familiar with TACT, it was a trial designed to test a favorite quack treatment for cardiovascular disease, chelation therapy. It is, as I have described many times in the past, an incredibly implausible therapy based on a hugely simplistic concept that because calcium accumulates in atherosclerotic lesions, then using chelation therapy could remove the calcium and reduce the lesions. Chelation therapy is a favorite treatment option recommended by naturopaths, and the claims made for it border on the absurd. It's frequently referred to as a "Roto Rooter" for the arteries that is a "safe and effective" alternative to angioplasty or coronary artery bypass.

It's not.

The first time I wrote about the results of TACT, its principal investigator Gervasio Lamas, MD, a professor of clinical medicine at the Columbia University Division of Cardiology and Chairman of Medicine at Mount Sinai Medical Center had just presented part of the trials results at the American Heart Association’s annual meeting back in November. As I noted at the time, the results were at best underwhelming, particularly given the methodological flaws. Basically, there was only a statistically significant difference between groups detected on subgroup analysis of diabetics, and there was no detectable difference in quality of life issues no matter how much Lamas tried to slice and dice the data. The next time around was a mere two weeks ago, when at the American College of Cardiology Meeting Lamas, apparently in pursuit of grinding out as many minimally publishable units (MPUs) as he could (or maybe I should say minimal presentable units), presented the results of the part of the study dealing with the high dose multivitamin and mineral solution that naturopaths so frequently like to administer with their chelation brew. As I explained again, the results were similarly underwhelming. Then, earlier this week, TACT was published online in JAMA. So underwhelming were the results again that I hadn't planned on blogging the study, given how extensively I've already written about it.

Then I saw a post over on Forbes by Harlan Krumholz entitled Chelation Therapy: What To Do With Inconvenient Evidence, and, oh, Lordy, I realized that I had no choice but to jump back into the breach and discuss the study some more because Dr. Krumholz's post was in essence a broadside against science and all those nasty skeptics who, to him, won't accept valid scientific results. It was painful to read and a big disappointment for Forbes given that my good bud Peter Lipson blogs at Forbes. Of course, my good bud Peter immediately (and correctly) took Dr. Krumholz to task for his misguided bloviation about TACT and us supposedly "close-minded" skeptics who won't accept "inconvenient" evidence. How could he resist? After all, Dr. Krumholz begins with a massive straw man:

What do we do with inconvenient evidence? Imagine studying a seemingly absurd practice that is used to an alarming extent by those who believe in it despite the lack of evidence – and finding that the intervention improves outcomes. And imagine that the people conducting that trial are famous scientists with impeccable credentials who have extensive experience with this type of investigation. Imagine that the practice is so out of the mainstream that the investigators cannot even posit how the treatment could reduce patient risk?

We live in a world of evidence-based medicine, where we are urged to base our medical recommendations and decisions on clinical studies. We base our guidelines on the medical literature and evaluate our practices by how well we adhere to the evidence. But what should we do with inconvenient evidence?

What indeed? The implication is that critics of TACT are questioning and rejecting the results because they are having trouble dealing with the results of a trial that seems to support a therapy that they find absurd. The problem, of course, is that is a simplification that is so massive that it's either intentional or reveals that Dr. Krumholz is almost completely unfamiliar with TACT, the sheer unethical design of the study, and the well-described problems with many of the sites at which the study were carried out, which were described in detail by Dr. R. W. Donnell in his most excellent Magical Mystery Tour of NCCAM Chelation Study Sites (part 1, part 2, part 3, part 4, part 5, part 6, part 7). I urge Dr. Krumholz to read all seven parts. As Dr. Donnell points out, only 12 of the 110 TACT study sites were academic medical centers. Many of the study sites were highly dubious clinics touting highly dubious therapies, including heavy metal analysis for chronic fatigue, intravenous infusions of vitamins and minerals (I could never figure out how infusing minerals could be reconciled with chelation therapy to remove minerals, but that’s just me), antiaging therapies, assessment of hormone status by saliva testing, and much more. Dr. Donnell also points out that the blinding of the study groups to local investigators was likely to have been faulty. So right off the bat, this study was dubious for so many reasons, not the least of which was that some of its site investigators were felons, a problem blithely dismissed by the NIH as being in essence irrelevant to whether the study could be done safely.

OK, OK, I get it. Just because several key investigators weren't exactly the sort of people who had demonstrated a high level of dedication to scientific rigor, ethics, or even honest doesn't necessarily mean the results of the trial aren't valid, but they sure as hell make me wonder, particularly given how minimally statistically significant the detected differences were.

Then there was the result of the FDA inspection of the highest accruing TACT site. It's brutal. In fact, it's more brutal than the Form FDA 483 that I just discussed about Stanislaw Burzynski. I kid you not. it's that bad. Read it and note observations that the investigators there:

The investigators didn't conduct the investigation in accordance with the signed statement and investigational plan. Several examples were given of shoddy procedures, prefilled forms, and failure to train personnel.
Failure to report promptly to the IRB all unanticipated problems involving risk to human subjects or others. Examples are given, including failure to report the deaths of patients on the study in a timely fashion (in one case the death wasn't reported to the IRB until four months later; in another case it was never reported at all). In other cases, adverse event reports were not submitted to the IRB.
Failure to prepare or maintain adequate case histories with respect to observations and data pertinent to the investigation.
Investigational drug disposition records are not adequate with respect to dates, quantity, and use by subjects.

In other words, the trial was a total mess at that site. One wonders what it was like at other sites, for instance the Marino Center.

It's probably worth looking at the paper itself a bit at this point. I didn't see anything there that made me change my original detailed assessment of the study from four months ago. You can go to the link for the full deconstruction. Every word applies to the published study, but let's look at some key points again. First, the primary endpoint (i.e., the aggregated serious cardiovascular events) did indeed show a modest difference, namely 30% of placebo subjects versus 26.5% of the EDTA chelation subjects (hazard ratio 0.82 for chelation). However, one notes that the result is just barely statistically significant, p = 0.035, with the 99% confidence interval for the hazard ratio ranging from 0.69 to 0.99. (The predetermined level for statistical significance for purposes of this study was 0.036; so this is statistically significant by the barest margin.) More importantly, if you look at the individual endpoints that make up that aggregate, there was no statistically significant difference in death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. Subgroup analysis (always a questionable analysis that requires replication, even when preplanned, as in TACT) purported to show a much greater benefit for diabetics, with a hazard ratio of 0.61 (p=0.002), while patients without diabetes showed no statistically significant difference in any of the outcome measures, including the aggregated total bad outcomes.

One question that came up last time had to do with other ingredients in the chelation mixture, specifically procaine and heparin, either of which could conceivably have had an effect on cardiovascular outcomes, particularly when given over the course of months intravenously. Another question that came up was how there could have been a better outcome in diabetics. One notes that the placebo solution contained 1.2% glucose in order to match the osmolarities of the control and experimental solutions. That could conceivably have contributed to a slightly worse outcomes in the control group even in the absence of a therapeutic effect due to chelation. Whatever the case, one notes that in nondiabetic patients there was no statistically significant detected benefit due to chelation therapy. Finally, only 65% of subjects finished all infusions, with only 76% finishing at least 30. That’s a high drop-out rate. Moreover, 17% withdrew consent, resulting in missing data. The investigators tried to correct for this in an online supplement, but these issues remain serious. They might not be so serious as to call into doubt the effect reported if there had been a much more convincing treatment effect, but when you get equivocal results such as this such issues loom much larger.

In fact, so messed up was this trial that it's hard to fathom the decision of JAMA's editors to publish it. Indeed, Kimball Atwood made a compelling case that, given all the ethical problems involved with this trial that any journal that published its results would be violating ethical norms established through the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, established by the International Committee of Medical Journal Editors.

JAMA's editors seem to know this in that they wrote an accompanying editorial justifying their decision to publish this trial using some of the lamest reasoning I've ever seen. First, they claim that they were really, really, really careful in reviewing the article to the point that they even read the Office of Human Research Protections (OHRP) reports, stating:

Moreover, we recognize that publication of research reports in influential journals can do harm. For instance, the debacle involving the study reporting an association between the measles-mumps-rubella vaccine and autism3 and the adverse effects that article had on immunization rates is an important reminder for all medical journal editors about the influence of their work on the attitudes, behaviors, and decisions of physicians and the nonphysician public.

Despite the limitations of the trial by Lamas et al and the continuing controversy surrounding TACT,4 once the scientific issues had been addressed satisfactorily, the decision to publish this report in JAMA involved consideration of several important factors. First, this NIH-sponsored study had been approved by institutional review boards at 2 academic medical centers, was conducted in compliance with federal regulations, and the OHRP investigation had determined that the corrective actions that had been taken were such that patient protection was not at risk.

Second, despite numerous setbacks, criticisms, and concerns, the funding agencies and the investigators (who include one of the preeminent cardiovascular researchers and one of themost respected statisticians) demonstrated courage and persistence in continuing this trial to its completion.

"Courage and persistence"? Give me a break. Dr. Lamas and his co-investigators might have demonstrated many things throughout the long and winding $30 million road of TACT, but courage and persistence were not among them. OK, maybe persistence, but let's not forget that a huge grant was at stake, and no investigator who's the PI of such a huge grant can afford to let it go and let the study crash and burn, although it would have been better for taxpayers and patients if TACT had been allowed to crash and burn. In fact, I get the feeling that the JAMA editors deep, deep down know that, too, as they published an editorial by Steven Nissen, who was utterly blistering in his criticisms of TACT:

Differential dropout in TACT suggests unmasking, but the problem of intentional unblinding is more concerning. The sponsors of the trial, the National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Complementary and Alternative Medicine (NCCAM), were unblinded throughout the trial. The National Institutes of Health policy unwisely allows the sponsor access to unblinded trial data, and both organizations sent observers to the closed sessions of the data monitoring committee. This gave them access to confidential data during each of the 11 interim analyses. The unblinding of the study sponsor represents a serious deviation from acceptable standards of conduct for supervision of clinical trials. If a pharmaceutical company sponsoring a trial were allowed access to actual outcome data during the study, there would be major objections. Like any sponsor, the NHLBI and NCCAM cannot be considered unbiased observers. These agencies made major financial commitments to the trial and may intentionally or inadvertently influence study conduct if inappropriately unblinded during the study.

Dr. Nissen also notes many other limitations in the design of TACT that undermine its reliability, including an observation that the primary endpoint should have only included the most objective and reliable components in its composite endpoint (death, stroke, and myocardial infarction) but also included "softer" endpoints (coronary revascularization and hospitalization for angina) that represented 318 of 483 events reported as primary end point event. He further noted that "if any unblinding occurred, investigator biases could potentially influence the decision to hospitalize or revascularize individual patients."

Dr. Nissen concluded:

Given the numerous concerns with this expensive, federally funded clinical trial, including missing data, potential investigator or patient unmasking, use of subjective end points, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy. The findings of TACT should not be used as a justification for increased use of this controversial therapy.

I couldn't have said it better myself.

Unfortunately, Dr. Krumholz sees it almost exactly the opposite:

The irony is that if a drug manufacturer had gotten this result, they would have celebrated. We have billion dollar drugs like niacin and fenofibrate and ezetimibe that have less evidence than chelation therapy has now. None of those drugs has contemporary outcomes studies showing benefit – and 2 of them (niacin and fenofibrate) have 2 recent negative trials.

And:

If we have little faith in chelation therapy, then it is hard to turn 180 degrees with a positive result and suddenly completely believe in it and recommend its use. Any trial can give an anomalous result and we need to be careful about jumping to a new position with each new piece of evidence. However, we cannot on one hand promote evidence-based medicine and on the other hand ignore what we do not like.

This is, as I've discussed extensively above, not what skeptics and critics are doing. Nor are they being hypocritical, as Dr. Krumholz implies insultingly. The ethical and scientifically rigorous conduct of clinical trials is a key component of evidence-based medicine. Trials that are sloppy in execution, carried out in large part at centers full of quacks (yes, quacks), and unethical are not good evidence-based medicine.

It's highly disappointing that Dr. Krumholz took the results of TACT at face value. As an academic cardiologist, he should know better, but it appears that he didn't even bother to read the paper. He didn't know that there was heparin in the chelation solution, and he didn't seem to have a problem with the addition of "soft" outcomes to the more typical "triple" aggregate outcome used in cardiology studies consisting of myocardial infarction, death, and stroke. In fact, as a commenter pointed out, even the triple composite outcome is not a patient-important outcome. Indeed, given how the individual endpoints that made up the composite endpoint showed no statistically significant differences, the composite endpoint can best be looked at as a way of trying to produce a statistically significant by adding endpoints that are not independent together and hoping that they aggregate to result in a statistically significant difference. I also note, as I have done for defenders of Stanislaw Burzynski, saying that other investigators do it too (or, as I like to call it, the "They do it too!" defense) is not a compelling retort, except perhaps among six year olds. Apparently both Dr. Krumholz and Forbes' Matthew Herper find such a retort compelling because they both use it in comments after Peter Lipson's post.

The bottom line is not, as Dr. Krumholz argues, that proponents of EBM are reflexively rejecting valid clinical trial results. It is rather that TACT is a trial testing a highly implausible therapy using methodology that was incredibly unlikely to produce a useful result. Worse, it was incompetently carried out at many sites and so riddled with problems that Dr. Nissen is quite correct to declare it useless and uninformative. Worse, it endangered patients without offering a reasonable likelihood of helping. If ever there was a dubious trial that is the poster child for using a Bayesian approach to clinical trials, it's TACT.

And if you're in the U.S., as I am, you paid for it to the tune of $30 million. That's $30 million that could have gone to actual, useful biomedical research. It's very sad that apparently neither Dr. Krumholz nor Matthew Herper can see that. It's even sadder still that JAMA published this tripe. In that JAMA is every bit as guilty as The Lancet was in 1998 when it published Andrew Wakefield's antivaccine nonsense. I can (sort of) accept the argument that all clinical trials should be published. However, that doesn't mean a clinical trial so riddled with scientific and methodological flaws should be published in JAMA. If published at all, TACT should have been published in some crappy, bottom-feeding journal, because that's all that it deserves. In a world where medical publishing worked properly, no journal in the top or middle tier would have touched this toxically bad manuscript with the proverbial ten foot pole.

Shame on JAMA! Shame on NCCAM and the NHBLI for funding this nonsense! And, yes, shame on all the shruggie cardiologists who are apparently unwilling or unable to look beyond the hype.

oracknows Wed, 03/27/2013 - 19:01

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http://www.bostonscientific.com/interventional-cardiology/products.html…;

the debacle involving the study reporting an association between the measles-mumps-rubella vaccine and autism

I would feel more comfortable - and more likely to listen sympathetically to his arguments - if he was mentioning in the text that this study has been retracted.
Because the way he presents it, one could believe that Wakefield's study is still legit and is another case of "inconvenient Evidence".
Which, for certain people, it is and it is, after all.

tl;dr: I would be more likely to consider if I am rejecting "inconvenient Evidence" if the good doctor was showing the ability to reject "inconclusive Evidence".

The Quackwatch piece on Edta treatment points out that each time a hypothesis for why Edta treatment might work was debunked, the practitioners of Edta treatment came up with another hypothesis. Each was demolished in turn.

It's a classic case of circular logic and of cart before the horse -- let's assume that this treatment does something useful, and try to explain why. The fact that it doesn't do something useful only reveals itself with difficulty, and by then, there is a group with a vested interest in arguing that it works and that there is a reason that it works. Sure sounds like a lot of other quackery, doesn't it?

Perhaps somebody can remind me of the historical progression, but if I recall correctly, this whole Edta thing predates the modern understanding of the fatty streak and of foam cells in the formation of clogged vessels.

Also, I seem to recall that long ago, there was a longevity treatment used in Europe that involved iv infusion of procaine. One Cal Tech professor used it and swore by it. I might be off on the particular molecule, but it was something in that class. It's curious that a similar compound is included in this kind of treatment.

a longevity treatment used in Europe that involved iv infusion of procaine

Gerotival.

I'm not too much bothered by the fact that the trial was published but more by the fact that the authors were allowed to claim the treatment was effective. The trial shows several scientifically interesting things: Chelation does nothing for non-diabetics. This eliminates 90% of the population as candidates for the "treatment". It shows an effect for diabetics, potentially due to other components of the mix. As there's no evidence that diabetic lesions and non-diabetic lesions are different, the postulated mechanism of calcium removal for lesion reduction is dead.
So all that is needed is a follow-on study designed to isolate the effect of the heparin vs the edta in diabetics. That will either show a very limited potential for chelation or drive a nail in so deep no one will be able to open that box of refuse again.
Of course, finding someone to risk burying chelation with a follow-on trial might be harder. NCCAM is unlikely to fund that and take out one of their few "success stories".

That’s $30 million that could have gone to actual, useful biomedical research.

Which, in this era of tight budgets, is quite a few R01s. As I've mentioned before, the kind of grants that I compete for (albeit from NASA and NSF) have a three-year cost of a bit more than 1% of this.

Given the level of funding, I can understand why the PI wants to publish something. But the reviewers are under no obligation to accept something like this for publication, and it sounds like they shouldn't have.

Were JAMA's editors going after a high-impact-even-if-low-quality publication, as certain other journals (notably Nature and Science) often do? I find their actions otherwise hard to explain here.

Actually, I would consider the RotoBlator to be the "rotorooter" of arteries given the method of treatment.

However, your link does indicate they are making a comparison to Roto-Rooter; I just don't get the analogy - it seems their method and science is more like "Draino" to me...

As fate and business plans would have it, our woo-meisters have created another chelation scenario which enables many more to benefit from the procedure:
no, I don't mean patients with CV issues but the woo-meisters themselves and patients with other conditions like ASDs, MS, Alzheimer's, cancer, you name it.

It seems they believe that chlorophyll is an effective chelator which can be administered orally, thus creating a market for pills and powdered green products that can be added to drinks. ( see NaturalNews store; Gary Null.com /Power Foods; and a thousand other sites).

They are especially enamoured of chorella ( see Adams' "clean" chlorella), spirulina, alfalfa and more general green products ( powdered spinach, broccoli etc); obviously, do-it-yourself-ers can buy juicers ( also available at these web stores).

So if you fear chemicals or don't have the time for IV, head over to your woo supplier NOW!

(I could never figure out how infusing minerals could be reconciled with chelation therapy to remove minerals, but that’s just me)

My first guess is that they get paid to dig the ditch and they also get paid to fill it.

If I'm recalling your past posts about chelation's dangers correctly, I'd also guess it makes the chelation less risky since extra minerals means there's a buffer staving off hypocalcemia and possibly other hypo-mineral problems.

@Denice Walter

Don't forget the miraculous chelation powers of rhubarb.

Chelation is old hat; there are better ways to keep the flow going.

"Original Luke guzzled gasoline.
He drank it down till his tube was clean.
Pine trees bent down to make a box
For ashes and a dream.
There's nothing much between."

- The Minus 5

Queen, Queen Caroline
Washed her hair in turpentine
Turpentine to make it shine
etc

"I can (sort of) accept the argument that all clinical trials should be published"

So maybe JAMA should institute a separate journal entitled "The Registry of Unsatisfactory Trials" and then all the crappy or inconclusive ones could at least be available to researchers who honestly want to know what's been tried and failed. If they wanted to be more gentle with the title they could substitute "Inadequate" for Unsatisfactory.

My uncle was in this trial, and I have some questions about it that I haven't found answers for. I'm hoping someone here might have a moment educate me.

First, I wonder what is meant by "Conflict of Interest" here. One of the authors, Theodore Rozema, obviously has some connection to Biogenesis Medical Center, which appears to be a site in the trial and thus I assume, the clinic offers chelation. However, the Conflict of Interest disclosure in the JAMA paper mentions nothing about it. I don't think they are hiding that Rozema has connections to Biogenesis, since it's listed in the supplement. I just wonder how it is that this isn't considered a conflict.

Second, with regard to withdrawals, it appears that there was an adjustment for withdrawn participants in the primary analysis, but is it clear if this adjustment was made for the subgroup analyses?

Thanks for anyone who can shed some light.

@Ignorant Kid: If the clinic is only offering chelation therapy via medical trials such as this one, and they don't charge patients to be in a medical trial, then it's fine. Otherwise, there would be no way to do a medical trial without somebody having a conflict of interest. It's also normal that at least one co-author of such a paper would be affiliated with each trial site. However, if one of the trial sites were already offering chelation therapy to paying patients for treating cardiovascular issues, that would be a conflict of interest.

Now, if Stanislaw Burzynski were to publish trial results of his antineoplaston therapy, he would have to disclose the conflict of interest that his clinic charges money for patients to undergo antineoplaston therapy. That may be yet another reason why Dr. B doesn't publish.

Todd W.,

Don’t forget the miraculous chelation powers of rhubarb.

Cautionary tale: as a child I had a habit of chewing on a stick of raw rhubarb from the large rhubarb patch at the end of our garden. I developed renal colic, presumably from the excessive amounts of oxalate I was ingesting, which was extremely painful and put me off ever eating rhubarb again. Rhubarb is almost as dangerous as broccoli (and kiwi fruit, of course).

Coriander leaf (cilantro) is also supposed to chelate heavy metals, though the evidence is slim to non-existent. I do sometimes wonder where these ideas come from.

Finally, some good news. If EDTA really is an effective treatment for atherosclerosis*, several McDonald's products, including Big Mac sauce, contain calcium disodium EDTA (PDF), so they should be effective against cardiovascular disease, in a high enough dose.

* It isn't, don't try this at home.

We have billion dollar drugs like niacin ...

Niacin a billion dollar drug? It's a B vitamin, it's been around for decades and it's cheap as dirt. It may not be effective, but then, neither is chelation.

Quick correction: Dr Chandra/Tru Med was not the highest enrolling TACT site. Trial sites are listed in order of subjects enrolled and Dr Rozema is first on the list with Dr Chandra second. The list of investigators is in the Supplemental Online Content for Lamas et al:
jama.jamanetwork.com/data/Journals/JAMA/926663/JOC130024_supp.pdf

This is surprising. In the response to FDA's inspectional findings at Dr Chandra's site, which is written by Drs Chandra and Lamas - mostly the latter based on prose style - we learn that as of June 2010, 2595 TACT infusions had been given at the site. See p. 12, para. 3
http://www.circare.org/tact/tactsite_responsetofdainspection.pdf

Dividing 2595 by 40 (the total # of infusions in TACT) gives 65 subjects enrolled at the site. But it's almost certain that not all subjects got 40 infusions because of the deaths noted in the inspection & because only 60% of subjects in the entire trial got all 40 infusions. If we divide by 30 we get 84 subjects (rounding down). 30 infusions may be too ambitious as well given overall numbers and Dr Chandra may have enrolled more subjects before the end of enrollment in Sept 2010.

Even so if Dr Chandra enrolled 84 subjects, Dr Rozema enrolled more. If we estimate that Dr Rozema enrolled 1 more subject than Dr Chandra, i.e. 85 subjects, 169 subjects were enrolled at 2 trial sites. This is nearly 10% of the total enrollment of 1708. Lopsided enrollments like this tend to confound data interpretation.

The inspectional findings that Orac linked to are nothing compared to Dr Lamas' response letter to FDA. It's quite astounding in fact.

@Krebiozen

I, too, would pluck stalks of rhubarb from the patch on my grandparents' farm and eat it raw. Never ate enough to cause any problems, though.

Little bit of trivia: in the Aubrey-Maturin series (Master and Commander) by Patrick O'Brian, a captain is prescribed some rhubarb for an illness. Thinking that "if a little is good, more must be better", the captain ingests far too much rhubarb and finds himself in the head for quite a long while (over a day, IIRC).

@Eric Lund.

Thank you for your reply. I saw that Biogenesis Medical Center does offer chelation therapy under services and they push it via testimonials and such on their website. Hard to imagine they don't charge for it. Anyway, thank you for your time. I appreciate the explanation.

Orac,

I'm a long time fan of your work. And I want to note, before I respond to your post, that my own reaction to the TACT results was not so different from yours. You can find it here:

http://www.forbes.com/sites/matthewherper/2012/11/04/civil-war-a-study-…

I'm not nearly so sure that all your arguments here are as convincing as you think. I am certain that in your haste to attack anything known as woo you are misreading Dr. Krumholz.

I know that you say you hate arguments from authority, but I'm a journalist, and what someone has accomplished does matter to me. Krumholz is probably best known for his work in reducing door to balloon time. He was also one of the loudest critics of Vioxx and said Merck's ezetimibe might be nothing more than a placebo. He's one of the most respected voices in cardiology. I'm pretty sure Steve Nissen still agrees with that. He has been a proponent of science-based medicine. He has something like 700 pubmed citations.

What I hear Krumholz saying is that although the benefits of chelation therapy are still questionable, it is impossible for him to look at a randomized controlled trial showing a positive result and not explore the possibility that there's something to it. (Maybe it's the heparin?)

On your composite endpoint argument, C. Michael Gibson, another of the country's top cardiologists, agreed on Twitter that it was a non-issue.

Krumholz's concern was that people are so eager to dismiss the results that they are refusing to grapple with the data. There is no question that, if this were a traditional new drug therapy, these results would be unlikely to pass muster with the FDA. Chelation is not evidence-based medicine.

But can you really argue that you're more certain there is absolutely nothing to chelation after seeing these results? More than that, can you really embrace the position that other respected doctors aren't allowed to grapple with the data and come to their own views?

I hear a lot of talk about TACT that starts with the assumption that it must be wrong, and, more than that, that things like this should not be studied. If we're going to live by the perspective that there should be no "alternative" medicine but only real medicine, there is a need to collect evidence.

Respectfully, I do think that if you're casting Krumholz as part of the enemy you're probably making a mistake.

Best,
Matt Herper

I'm no fan of chelation therapy, so take no position on whether the actual scientific data generated by this study should be rejected out of hand or not. However, you do need to be prepared to explain why your criticisms of trial design, particularly the endpoints, should not be equally applicable to other cardiovascular trials of more favored modalities. It is extraordinarily common for the primary endpoint in studies of drugs, or even invasive procedures for which treating physicians are totally unblinded, to be a composite such as "death from any cause, heart attack, stroke, revascularization, or hospitalization for cardiovascular causes." Then the study reports that these events were cut by 40% in the verum group, and the news media claim that the product "Saves Lives." Only by reading the fine print can you learn that the vast majority of events prevented were stentings and hospitalizations, that strokes and heart attacks were nonsignificantly reduced and total deaths not reduced at all. Oh yes, and non-cardiovascular hospitalizations, e.g., for drug side effects, do not count in the primary outcome, as if patients dislike hospitalizations only if they are for heart problems. Indeed, this appears to be a trifle unethical. Would you agree?

Just to make sure I am reading this correctly:
The treatment arm (chelation) contained heparin, a known blood thinner.
The control arm (placebo) did not contain heparin.

So, the "control" arm of the study (the placebo) was not in fact a control at all because it was missing an ingredient with an known or suspected impact on the study outcomes.

If I tried to set up an experiment with a "control" like that my boss would bite my head off.

Science: you're doing it wrong.

I think the money thing is overrated. The biggest problem, even if the clinic only ever performed chelation for free, is that they were already performing this treatment while stating publicly (via their website) that it has lots of benefits other than the FDA-recognized use. Obviously there is a huge motivation to find evidence which supports what they had already been doing and saying without evidence.

But can you really argue that you’re more certain there is absolutely nothing to chelation after seeing these results?

Yes. In fact, even if I grant you the issue of composite endpoints, there are plenty of other issues with TACT to make its results completely unreliable, which have been detailed by Kimball Atwood.

As for Dr. Krumholz, I am not attacking him as an enemy of SBM. I am pointing out that in this case he screwed up and that he really should know better, particularly given that he's such a respected academic. Basically, it was very clear from his post that he was not at all familiar with the numerous issues with the trial that doomed it from the start to the point that any result it produced would have to be really striking to overcome them. Its results were anything but striking, for the reasons I explained ad nauseam.

Also, if Dr. Krumholz is going to write a blog that strongly implies that supporters of EBM are hypocrites exercising a double standard with respect to evidence, dogmatic, or otherwise close-minded for not accepting TACT at face value, he should be prepared to take the criticism he's going to going to receive, particularly given that it's clear from his comments that he didn't read the paper very carefully and is unfamiliar with the history of TACT. In fact, I found his implication that SBM supporters are hypocrites for not being more open to the results of TACT insulting.

As for composite outcomes, I'm sorry, but they're dubious at best and misleading at worst; they are also very poorly reported and widely abused. I can provide references if necessary to support my position. Not surprisingly, most of the papers are from cardiovascular trials, where this deceptive practice seems to be most common as far as I can tell.

As I said, though, you can completely leave out the issue of the composite endpoint, and TACT would still be crap.

I'm flattered that you are a fan. As a fan, you must be aware that I rarely pull punches. I like to think that the fact that I restrained myself from using some of my favorite terms for quackery supporters (e.g., "burning stupid") should show that I don't consider Dr. Krumholz to be a woo. I just consider him to be disappointingly mistaken and uninformed on this one trial.

But can you really argue that you’re more certain there is absolutely nothing to chelation after seeing these results? More than that, can you really embrace the position that other respected doctors aren’t allowed to grapple with the data and come to their own views?

This is weren prior plausibility and Bayesian analysis comes in. I can't do the maths, as I don't know the figures or previous research well enough, but if before, we could say it was 98% certain chelation does not work, then when we include this slight benefit from one poorly controlled study, it is unlikely to shift that figure much.
As a related example, if 10 studies find absolutely no benefit to a treatment, and an eleventh comes out and finds a small one, we don't throw out the previous 10 and just focus on the one that worked (well, we don't if we are aware of them. If they didn't get published this won't help).

I do not endorse chelation therapy, and do not view the TACT results as providing actionable evidence for regulatory decision making or for guiding clinical practice. However, notwithstanding the flaws in trial design and conduct, I would like to make the following observations regarding TACT.

1. For a variety of reasons, I am not a big fan of the type of composite endpoint used in TACT. However, the so called 'soft' subjective components of CV hospitalization and revascularization are more prone to ascertainment and misclassification error, and therefore likely to bias the results towards the null. While this might be anti-conservative for safety assessment where one is interested in ruling out unacceptable risk, it can be overly conservative for efficacy assessment. The choice of these 'more prevalent but less important' endpoints is driven primarily by trial feasibility considerations.

2. The amount of missing data, while vexing, is not unexpected given the onerous treatment protocol involving multiple infusions over a prolonged period of time. The missing data can challenge the interpretation of trial results, but the claim that it invalidates the results is not supported by careful examination of the data provided in the supplement. There does not appear to be major imbalances in either the key prognostic covariates or in the reasons for 'missingness' amongst the 2 randomized groups in those who dropped out. Thus, the potential for 'informative censoring' appears to be minimal. By the way, the problem of missing data (and sloppy trial conduct) is quite common even in clinical trials run by academic research organizations of the highest repute!

3. There are several examples in medicine (antioxidant vitamins, hormone replacement therapy, magnesium for MI, anti-reperfusion injury therapy, etc.) that have shone the spotlight on the slippery slope argument of plausibility. As Thomas Huxley said it best, "the tragedy of science, the slaying of a beautiful (plausible) hypothesis by ugly facts!"

4. The principle of equipoise, an ethical prerequisite for patient randomization and enrollment, would require a pretrial null hypothesis probability of 50%. If the pretrial null probability is 98% as suggested by G. Shelley, then how can one ethically justify conducting the trial to begin with? Surely, the sponsor, NHLBI, must have given it some thought!

5. The p value of 0.03 translates into a minimum Bayes' factor of 0.09, which reduces the null probability from 50% pretrial to about 9% post-trial. While this does not represent strong evidence against the null, it does reduce the level of skepticism surrounding chelation therapy.

6. There is clearly a double standard when it comes to accepting the results of trials evaluating so-called dubious quack cures such as chelation versus trials assessing promising de rigueur cures such as gene transfer or stem cell therapy.

Finally, while the debate surrounding TACT is clearly warranted and welcome, I hope it generates more light than heat.
Cheers

@ Sanjay:

4. Why in the world would you make that assumption? Trials are routinely done, by many of the same people, of treatments with pretrial null probabilities of greater than 99.9999% (homeopathy or reiki, for example).

5. #4 kills this argument too; the null probability pre-trial was much much much greater than 50%.

6. Evidence for said double standard? Orac regularly calls out mainstream research when it is faulty.

Sanjay Kaul,

If the pretrial null probability is 98% as suggested by G. Shelley, then how can one ethically justify conducting the trial to begin with? Surely, the sponsor, NHLBI, must have given it some thought!

That was the question being asked by sceptical bloggers several years ago.

Well, I did say I just made up the 98% figure as an example, but I don't think it too unlikely. As others mentioned, people still study homeopathy and get grants to do that and I'd argue that the pre-trial null plausibility is much greater.
Even if 98% is too high, the pre-trial value can't be 50%. That might be the case if it had never been investigated at all (though even then, you'd have to fail to take into account biological plausibility), but previous trials will have shifted this, otherwise you get the contradictory result that after this trial you are at a 9% probability, but if someone starts a new trial, that jumps back up to 50%.

OK, let's assume the pretrial null probability is 75% (and not 98%), the TACT evidence (howsoever flawed), will moderate the post-trial null probability to 22%, which means that more likely than not, chelation is associated with a non-null treatment effect.

If one is a skeptic (pretrial null probability >50-75%), why would one expose one's patients to the hazard of chelation?
Conversely, if you are an enthusiast (pretrial null probability <25-50%), why would one deny their patients the benefits of chelation?
In principle, one can ethically justify randomizing one's patients if one is not overly sure of its treatment effect, i.e., suspending one's belief as reflected in a pretrial null probability of 50%.

Bottom line, in my opinion, the arguments that the TACT results are dubious or not valid are overstated!

@Sanjay Kaul,

On what basis do you believe that "arguments that the TACT results are dubious or not valid are overstated!"? If the flaws in the studies are as significant as some claim, your discussion of statistics is rather pointless - calculating error bars and p values based on skewed observations produces meaningless numbers.

@Sanjay Kaul

Thank you for your comments. Before I go on, I have to mention that the concept of equipoise doesn't require a pretrial prior probability of 50%. It requires that there be genuine and substantial uncertainty over whether the treatment is effective, particularly when the trial is placebo-controlled, where the control is in essence doing nothing. Or, perhaps a better way of putting it is that there has to be real uncertainty over whether the risk/benefit ratio is favorable, preferably with preclinical and clinical evidence suggesting that it is. TACT met none of these criteria, nor did it meet the standards of the Helsinki Declaration:

Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation.

And:

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.

I note that there was no compelling clinical or preclinical evidence that chelation therapy has significant efficacy against atherosclerotic cardiovascular disease, and we know that chelation therapy can cause harm; so the risk was not minimal. Moreover, as demonstrated in the links I provided, many, if not most, of the site investigators carrying out the trial do not have appropriate scientific training and qualifications.

As for the composite endpoint, I never could figure out why they are so prevalent in cardiology research. In oncology, we tend to frown on them in our clinical trials—and with good reason. I'm also not particularly convinced by your argument, at least in this case, that a composite endpoint is more conservative, given that not a single one of the components that made up the composite endpoint reached statistical significance. There are so many other issues that have been widely discussed in the blogosphere about TACT that I could only briefly touch on here about how the trial was completely unethical and violated the principles of informed consent. Moreover, not everyone agrees that the dropout rate is not a problem:

http://bigstory.ap.org/article/doctors-debate-value-fringe-heart-treatm…

Even if we take the trial at face value and ignore all the major problems with its design and how it was carried out that almost certainly make its results completely unreliable (as Dr. Nissen points out), all we're left with are two findings. First, chelation therapy does absolutely nothing for quality of life. Second, it provides zero benefit for patients who are not diabetic. The only reason for a barely statistically significant difference in the overall population boils down to the modest benefit reported in diabetics. Personally, I strongly suspect that that benefit in diabetics is not real (for all of the reasons I discussed above and here), but let's for the moment say it is, just for the sake of argument. In that case, what the recommendation from this trial should be is that no non-diabetic with cardiovascular disease should be treated with chelation therapy because it definitely does not work for them. It should also be stated that no claims for improvement in quality of life and symptoms should be made, because chelation does nothing for that, either. Interestingly, even Lamas doesn't suggest that chelation should be used even in diabetics.

Regarding the issue of prior probability, it's not overstated as you claim. In fact, I like to point to the masterful analysis of TACT by Kimball Atwood, Elizabeth Woeckner, Robert S. Baratz, and Wally Sampson published five years ago in Medscape. Besides detailing at huge length why the trial is unscientific and unethical, Atwood et al made this prediction:

The trial, moreover, is unlikely to yield “an informative negative result[49]” 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.[4,5] 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.[7] There is ample, additional opportunity for mischief, and ample reason to think that several co-investigators are inclined to make it.[7] The statistical analyses will not be Bayesian.[322–324]

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[29]” in the minds of apologists. Dr. Lamas himself has made much of 2 or 3 “tantalizing positive secondary outcomes[29]” 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.[25] 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.

Sounds eerily like the outcome to me, except that the outcome arguably showed even fewer "positives" than Atwood et al had predicted. All that for $30 million. What a waste.

For more:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438277/?tool=pubmed
http://www.sciencebasedmedicine.org/index.php/the-tact-is-at-least-as-b…
http://www.sciencebasedmedicine.org/index.php/the-trial-to-assess-chela…

Thank you for responding to my comments.

“Before I go on, I have to mention that the concept of equipoise doesn’t require a pretrial prior probability of 50%. It requires that there be genuine and substantial uncertainty over whether the treatment is effective, particularly when the trial is placebo-controlled, where the control is in essence doing nothing.”

How would you quantify genuine and substantial uncertainty?

"I note that there was no compelling clinical or preclinical evidence that chelation therapy has significant efficacy against atherosclerotic cardiovascular disease, and we know that chelation therapy can cause harm; so the risk was not minimal."

Is there robust evidence it is not effective or it is harmful? The answer has a bearing on quantifying uncertainty.

"I’m also not particularly convinced by your argument, at least in this case, that a composite endpoint is more conservative, given that not a single one of the components that made up the composite endpoint reached statistical significance."

I don’t think the composite endpoint is conservative! What I am saying is that inclusion of soft and somewhat subjective endpoints such as CV hospitalization or revascularization increase the potential for ascertainment error and misclassification that typically biases the results towards the null. So, if the objective of the trial is to prove superiority, then the bias will operate against it (conservative). On the other hand, if the objective of the trial is to prove noninferiority (rule out unacceptable risk), then the bias will operate in its favor (anti-conservative).

"There are so many other issues that have been widely discussed in the blogosphere about TACT that I could only briefly touch on here about how the trial was completely unethical and violated the principles of informed consent. Moreover, not everyone agrees that the dropout rate is not a problem:
http://bigstory.ap.org/article/doctors-debate-value-fringe-heart-treatm…"

The commentators quoted in the AP story in November 2012 are correct in expressing their surprise at the pattern of differential missing data (more in placebo group). However, without access to the details of the data (provided in the JAMA supplement), they had no way of assessing whether this could lead to informative censoring. Careful scrutiny of the data doesn’t lead to the conclusion that informative censoring did indeed occur in favor of chelation. Moreover, the results of the sensitivity analyses don’t support this assertion. I acknowledge that missing data are problematic in general as they challenge the interpretation of the overall results, but the onus is on those who claim that it invalidates the results to prove so!

"Personally, I strongly suspect that that benefit in diabetics is not real (for all of the reasons I discussed above and here), but let’s for the moment say it is, just for the sake of argument. In that case, what the recommendation from this trial should be is that no non-diabetic with cardiovascular disease should be treated with chelation therapy because it definitely does not work for them."

Your interpretation about treatment effect in diabetics is not unreasonable. Even though the subgroup analysis was prespecified, and the interaction is quantitative (difference in magnitude of effect), adjustment for multiple comparisons would have weakened the interaction term. Your presumption that TACT provides actionable evidence for clinical practice is not endorsed by anyone including the TACT investigators. The best case interpretation of the data is that the evidence is inconclusive. Ideally, under such circumstances, the only worthwhile recommendation should be ‘additional studies are warranted to adjudicate the uncertainties’. That is how science and knowledge should progress.

"The trial, moreover, is unlikely to yield “an informative negative result[49]” 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.[4,5] 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.[7] There is ample, additional opportunity for mischief, and ample reason to think that several co-investigators are inclined to make it.[7] The statistical analyses will not be Bayesian.[322–324]"

Here is my Bayesian analysis of TACT which you might find instructive:
Evidence (likelihood) = 0.82 (0.69, 0.99)
Prior (skeptical) = 1.0 (0.75, 1.33) (this means that the mean is centered on null, and there is only 10% probability of the effect being >25% risk reduction or >33% risk increase; many would argue that this is a reasonably skeptical prior distribution)
Posterior = 0.87 (0.75, 1.02), i.e., the probability of a >13% risk reduction is 50%, and the probability of a >10% risk reduction is 66%.
So if we start from a position of skepticism, integrating the results of the TACT trial reduces the degree of skepticism. This is exactly how Bayesian analysis helps upgrade knowledge and information.
One would require a prior of 2-fold increase in CV risk with chelation (not supported by evidence to my knowledge) to completely nullify the results of TACT trial, an arguably IMPLAUSIBLE conjecture!

There are many cases where previously established beliefs are later proven to be wrong or require substantial revision.

To suggest that this study should not have been published would be to support publication bias and is the antithesis of proper science.

The contention inferring that this study somehow shows that chelation is ineffective clearly shows the kind of double standard and willingness to misinterpret results that exists in the profession.

@Cvrai - proper studies stand up to scrutiny. If you read the study, the critique, and the follow-up, you'd understand that there were serious problems with the study design, implementation and overall methodology - saying the study is bad isn't saying it shouldn't have been published, it is saying that it should stand on its own merits, which unfortunately, it does not.

@Lawrence - What I see is a double standard. The shortcomings of the current study are standard and overlooked in others. What I see is a misleading interpretation. I don't see how from any objective standard someone could interpret the results as somehow showing chelation is now more worthy of being dismissed, but astonishingly that is how an accompanying editorial spins it.

For any who believe in the proper pursuit of science such displayed bias should reek. People who see such incongruities are right to grow more skeptical of those who would apply such double standards.

I am aware of other studies on other health issues that have been relied upon for policy that have gaping problems. For example the Seven Countries Study and the Oslo Diet-Heart Study. Compare this study to those studies and tell me this study even with all its flaws is really fundamentally worse. Tell me why this blog isn't up in arms in the same way when those studies that I have mentioned are actually used to support current policies despite their glaring weaknesses.

The kind of criticism seen here is selectively applied. It is because the topic explored is chelation a therapy that has become associated with alternative medicine. As others have pointed out if this was some novel drug the chances it would illicit much passion would be low.

That means there is an outside issue at work here: hostility towards alternative medicine. Going by the reactions hostility even in the face of evidence. Such passion has no place in processes that claim to be scientific.

The shortcomings of the current study are standard and overlooked in others

Cvrai, you've provided no evidence for this statement. If you want to be taken seriously, try engaging with the actual study instead of blanket statements like this.

@Cvrai

Going by the reactions hostility even in the face of evidence.

What evidence? I've seen assertions, but no evidence. Also, you may want to peruse this blog a bit more, as you will find that Orac (and the regulars) do address "conventional" medicine and "novel" drugs. For instance, take Stanislaw Burzynski's "novel" (well, 30+-year-old) drug, antineoplastons, as an example that has been addressed recently (and with many, many posts).

Try to avoid making sweeping declarations of bias like that, especially when you have yet to do your homework.

Tell me why this blog isn’t up in arms in the same way when those studies that I have mentioned are actually used to support current policies despite their glaring weaknesses.
Perhaps because those studies were published more than 40 years ago, and that their prinicple findings regarding diet and health risk have been refined and upheld by multiple additional studies during the ensuing 4 decades?

The Seven Countries Study was the first to examine associations among diet, risk, and disease in contrasting populations beginning in1958 and ending in 1971. While today we can point to genuine criticisms of it's methodology (notably the manner in which they selected the populations studied and the limited populations units used for comparison, in 1958 it was state of the art and the idea of looking for ecologic correlations ground breaking.

The Oslo-Diet heart study was published in 1966, and again was among the first of these types of ecologic correlation studies.

The TACT study on the other hand was begun in 2003. What's their excuse?

Arrgh!

Cvrai,
It is interesting to compare TACT with the Oslo Diet-Heart Study (the Seven Countries Study was an epidemiological study, not an interventional one).

TACT had marginally statistically significant results for serious cardiovascular events:
n = 1708, 30% of placebo subjects versus 26.5% of the EDTA chelation subjects with p = 0.035
The Oslo Diet-Heart Study also had marginally statistically significant results for serious cardiovascular events:
n = 412, 39% of control subjects versus 30% of diet patients with p = 0.05

TACT showed (at best) at 3.5% reduction in serious cardiovascular events, whereas the Oslo Diet-Heart Study reduced reduction in serious cardiovascular events by 9%. The current consensus view is that diet modification has only a minor effect on serum cholesterol levels, but that even these small changes can result in improved cardiovascular outcomes, so they are worth pursuing before resorting to medication. That seems consistent with not only these studies but a whole raft of other more recent evidence - see Steinberg's 'Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy'.

Above should read "the Oslo Diet-Heart Study reduced reduction inserious cardiovascular events by 9%".

@AdamG

Look at earlier comments regarding composite endpoints and their standard usage in similar studies. Also see below.

@Todd W.

Are you suggesting the results of the TACT study are merely assertions and not evidence?

@JGC @Krebiozen

The Seven Countries Study and Oslo Diet-Heart Study old as they are still mentioned in defense of the current policies and guidelines. TACT isn't. I've even seen the Oslo study referred to as among the best studies of its kind. I wonder what you would think though if you knew that the participants in that study were provided sardines in cod liver oil and instructed to eat seafood in place of meat and eggs. Compare that to the small presence of heparin in the TACT trial and the TACT trial doesn't seem so bad. Consider also the recent findings on sugar and refined carbohydrates and one might want to ask if all the studies of the past properly accounted and adjusted for their effect. Current nutritional policies are built on sand. This is far more scandalous than anything chelation related, but all I hear are crickets chirping instead of full-throated voices from those who would insist on science-based evidence.

@Krebiozen

I haven't read the Steinberg link in detail but there is some question as to whether statins are effective due to their effect on cholesterol or some other pathway. It may well be they are beneficial because of their effect on inflammation. A recent study shows that omega 3s seem to lose their efficacy in the presence of statins. Maybe statins interfere with omega 3 but maybe omega 3 and statins work in the same way? Reducing cholesterol wouldn't appear to be that mechanism however. There are some studies that show that those with the lowest levels of cholesterol (supposedly good) had the highest incidence of mortality.

Cvrai,
I though I detected a hint of cholesterol skepticism - I suggest you read Harriet Hall's criticism of their ideas before you go too much further down that particular rabbit hole. Read the Steinberg series too, or at least skim through the summaries. The cholesterol skeptics are wrong - they cherry-pick their way through the literature, ignoring large amounts of evidence that contradicts their claims.

The Seven Countries Study and Oslo Diet-Heart Study old as they are still mentioned in defense of the current policies and guidelines. TACT isn’t. I’ve even seen the Oslo study referred to as among the best studies of its kind.

They are still mentioned because they were the first attempts to look at dietary interventions to reduce cardiovascular disease. They are part of a very large body of evidence that supports the consensus on diet and cardiovascular disease. TACT has no such body of evidence, nor scientific plausibility to support it.

Consider also the recent findings on sugar and refined carbohydrates and one might want to ask if all the studies of the past properly accounted and adjusted for their effect. Current nutritional policies are built on sand.

I disagree. Could you be more specific about which current nutritional policies you are referring to, and what evidence contradicts it?

I haven’t read the Steinberg link in detail but there is some question as to whether statins are effective due to their effect on cholesterol or some other pathway. It may well be they are beneficial because of their effect on inflammation. A recent study shows that omega 3s seem to lose their efficacy in the presence of statins. Maybe statins interfere with omega 3 but maybe omega 3 and statins work in the same way? Reducing cholesterol wouldn’t appear to be that mechanism however.

We know that reducing cholesterol by any means, whether through diet, cholestyramine, statins etc..has a beneficial effect on cardiovascular disease. So it seems likely that statins also exert at least part of their beneficial effect on cardiovascular disease by reducing cholesterol, but they also reduce all-cause mortality, which may be due to their anti-inflammatory effects.

There are some studies that show that those with the lowest levels of cholesterol (supposedly good) had the highest incidence of mortality.

That claim is a particular bugbear of mine; having worked in clinical biochemistry I know very well that very sick people have low serum cholesterol, but they also have low serum albumin and low total proteins, because they have poor nutrition and often, in the case of cancer patients, cachexia. Low cholesterol is a result, not a cause of serious illness. Older people with chronic diseases also tend to have low cholesterol because the people with high cholesterol already died of cardiovascular diseases, not because their low cholesterol made them sick.

Cvrai,
There's a paper on the interaction of statins and omega 3 here. I wasn't aware of this, so thanks for drawing my attention to it, though I'm not sure what to make of it yet.

I looked at the Harriet Hall link. I cannot say I'm impressed. THINCS presented more citations and the comments section is filled with comments lambasting Hall's argument.

If dietary cholesterol only has a small effect as Hall admits, current dietary guidelines to avoid saturated fats at best have minimal relevance. If statins work to reduce CVD and mortality by pathways other than reducing cholesterol then the cholesterol question it seems still remains unresolved contrary to Steinberg's claim.

Worse if you combine the recommendation to avoid saturated fats with the use of statins one possible deleterious effect would be to avoid meat (a main source for coenzyme Q10) while taking a medication associated with weakening muscles.

We know that reducing cholesterol by any means, whether through diet, cholestyramine, statins etc..has a beneficial effect on cardiovascular disease.

This is still debatable. Even by Steinberg's estimation this question was settled only by the advent of statins. But if statins work via other pathways.... Correlation yes; causation still room for doubt. Unconvinced? Read the comments of a developer of a drug that shows potentially stronger cholesterol lowering effects than statins. Statins will still remain the mainstay because they are proven to reduce events. Perhaps if that drug is approved and with more studies a more definitive answer to the question can be given.

I keep seeing the phrase "the totality of evidence" used by Hall and medical organizations to justify their views but in my own personal attempts to look at the "totality of evidence" I find significant omissions and skewed interpretations and have a reaction similar to the one found in this paper.

Cvrai,

I looked at the Harriet Hall link. I cannot say I’m impressed. THINCS presented more citations and the comments section is filled with comments lambasting Hall’s argument

You don't settle a scientific debate by putting citations that support or do not support your hypothesis into two piles, with the biggest pile winning, though if that were the case the lipid hypothesis would come out well ahead. You need to look at the literature as a whole, including the quality of the studies, how well confounding factors are controlled for prior plausibility, epidemiological evidence and our understanding of atherogenesis, among other factors. On the basis of this evidence the great majority of doctors and scientists in this field accept the lipid hypothesis as proven. It is only a minority of so-called skeptics that don't accept this, and I think it's fair to describe many of them as cranks, including some of those "lambasting" Dr. Hall.. Dig a bit deeper and you will find their claims don't stand up to close scrutiny.

I suggest you spend a bit of time looking at those THINCS citations and compare what they actually say to what THINCS claims they say. Also, look at all the citations in Steinberg that THINCS pointedly ignores. When I did this a few years ago I was shocked at how THINCS deliberately misrepresented studies, cherry-picked only studies that supported their beliefs, and even cherry-picked bits out of studies, ignoring the very large amount of evidence that completely contradicts their position. Don't take my word for it, look for yourself. Compare the citations Harriet Hall provides and see if they say what she claims they do.

If dietary cholesterol only has a small effect as Hall admits, current dietary guidelines to avoid saturated fats at best have minimal relevance.

It's not a matter of Hall admitting this, we have known this for decades. Only a minority of cholesterol in the blood is dietary, most is made in the liver, that's why statins were developed, to reduce cholesterol synthesis. The conventional approach in patients at high risk of cardiovascular disease is usually to try lifestyle modification to reduce cholesterol first, and resort to medication if this fails. Isn't a 14% reduction in cardiovascular risk well worth pursuing?

If statins work to reduce CVD and mortality by pathways other than reducing cholesterol then the cholesterol question it seems still remains unresolved contrary to Steinberg’s claim.

If? Steinberg's "claim" is supported by a huge mountain of evidence gathered over several decades. We know how statins work, and we have a pretty good idea of how reducing circulating LDL cholesterol reduces atherosclerosis. Statins may have other effects through other mechanisms, but we can be close to certain that their effect on CVD is through lowering LDL.

Worse if you combine the recommendation to avoid saturated fats with the use of statins one possible deleterious effect would be to avoid meat (a main source for coenzyme Q10) while taking a medication associated with weakening muscles.

There's more CoQ10 in soy bean oil, olive oil, grapeseed and some fish than there is in beef, so that isn't necessarily a problem. Some doctors prescribe CoQ10 to patients on statins who suffer side effects, which may be a good idea, though the evidence still isn't very clear.

We know that reducing cholesterol by any means, whether through diet, cholestyramine, statins etc..has a beneficial effect on cardiovascular disease.

This is still debatable. Even by Steinberg’s estimation this question was settled only by the advent of statins.

It really isn't debatable. Most scientists were convinced before the advent of statins, and there really isn't any reasonable doubt any more.

But if statins work via other pathways…. Correlation yes; causation still room for doubt. Unconvinced?

Deeply unconvinced. I'm not really clear what you are arguing here. Are you suggesting that saturated fats do not increase cardiovascular risk? That replacing them with PUFAs doesn't reduce cardiovascular risk? I think the evidence for this is compelling. I see a lot of people complaining about carbohydrates, but I think the evidence shows that consuming more calories than we expend, resulting in obesity, is the real problem with carbohydrates.

Read the comments of a developer of a drug that shows potentially stronger cholesterol lowering effects than statins. Statins will still remain the mainstay because they are proven to reduce events. Perhaps if that drug is approved and with more studies a more definitive answer to the question can be given.

I don't understand what your argument is here either. Statins will remain the mainstay until the new drug is proven to be safer and/or more effective. It is very likely that a further reduction in LDL will further reduce cardiovascular risk.

I keep seeing the phrase “the totality of evidence” used by Hall and medical organizations to justify their views but in my own personal attempts to look at the “totality of evidence” I find significant omissions and skewed interpretations and have a reaction similar to the one found in this paper.

I can only suggest you plow through all five parts of Steinberg's review, which discusses "the totality of evidence" in detail. This is a complex area, there's a lot of evidence of varying quality, and you really do need to look at the forest as a whole with a critical and skeptical eye, not just a few interesting-looking trees, or you may get a very distorted view, like that promoted by THINCS.

I've seen stretched arguments from some THINCS members in advancing their positions—but I've also seen the same from those promoting the current dogma. In fact you see it quite vividly in this TACT chelation study where the results are ignored or massaged to conform to predominant thinking rather than presented in light of their significance.

If? Steinberg’s “claim” is supported by a huge mountain of evidence gathered over several decades.

Would you be referring to the same mountain of evidence that was the basis for the low-fat American Heart Association Prudent Diet that was dumped in favor of the Mediterranean Diet after it was humiliatingly found to be inferior? The same mountain of evidence that castigated low-carbohydrate diets before direct RCT diet comparisons were actually done?

We know how statins work, and we have a pretty good idea of how reducing circulating LDL cholesterol reduces atherosclerosis.

You stated previously you were unaware of the recent research suggesting statins interfering with omega 3. Moreover from what I can tell how omega 3 works is still not well understood nor is omega 6. If we don't know how those work I suggest we still have a significantly unclear picture.

Are you suggesting that saturated fats do not increase cardiovascular risk? That replacing them with PUFAs doesn’t reduce cardiovascular risk?

Which saturated fats are you talking about? Palmitic and myristic acids? I'll agree that they likely increase risk. Stearic and lauric acids? No and possibly even reduce risk. Saturated fats as a group may fall in-between whole grain and refined carbohydrates in terms of association with increased CVD risk. So it might actually be apropos to call saturated fats neutral and from that point-of-view the better way to phrase your question is "Do PUFAs lower the risk of CVDs in comparison to saturated fats?"

Now the evidence for the beneficial effects of omega 3 seem to be quite clear but omega 6 is another story.
Are you aware of the theory that omega 6 is actually harmful and promotes inflammation? It appears that there isn't really that strong a body of research showing the benefits of omega 6 alone. In fact a recent update to the Sydney Diet Heart Study, one of the handful equipped to test its effects on its own showed negative results, significantly worse than for saturated fats.

One of the other interesting suggestions of the statin and omega 3 paper I mentioned earlier if I read it right is how statins interact with omega 6 in place of omega 3. That is a potentially significant mechanism if the omega 6 is dangerous theory is true.

This is a complex area, there’s a lot of evidence of varying quality, and you really do need to look at the forest as a whole with a critical and skeptical eye, not just a few interesting-looking trees, or you may get a very distorted view, like that promoted by THINCS.

You are right this is a complex area but the current dogma has been prevalent for over 30 years and has seen a concomitant rise in obesity with no lowering of CVD incidence. The superiority of the Mediterranean diet and low-carb diets contrary to expectations strongly call into question the assumptions of the prevailing wisdom.

Cvrai,

We’ve seen stretched arguments from some THINCS members in advancing their positions—but I’ve also seen the same from those promoting the current dogma. In fact you see it quite vividly in this TACT chelation study where the results are ignored or massaged to conform to predominant thinking rather than presented in light of their significance.

You described the 14% reduction in cardiovascular risk we see in a systematic review of the effects of modification of dietary fat in 65,508 participants as being of "minimal relevance", yet you appear to think the 3.5% reduction in cardiovascular risk we see in 1,700 participants in the TACT study is significant? Who is massaging the figures here?

Would you be referring to the same mountain of evidence that was the basis for the low-fat American Heart Association Prudent Diet that was dumped in favor of the Mediterranean Diet after it was humiliatingly found to be inferior? The same mountain of evidence that castigated low-carbohydrate diets before direct RCT diet comparisons were actually done?

No, the mountain of evidence that supports the lipid hypothesis, in contrast to the tiny amount of poor quality evidence that supports chelation, which is what I thought we were discussing. You appear to be trying to steer the discussion towards other more controversial areas of nutrition that I agree are less well-supported by good evidence.

As I have stated many times here, my opinion on diet goes little further than Michael Pollan's maxim, "eat, not too much, mostly plants". I think the main problems we see in the developed world are from people eating too much, period.

You described the 14% reduction in cardiovascular risk we see in a systematic review of the effects of modification of dietary fat in 65,508 participants as being of “minimal relevance”, yet you appear to think the 3.5% reduction in cardiovascular risk we see in 1,700 participants in the TACT study is significant?

I was not talking about statistical significance, but significance in the body of research on chelation. The TACT study is significant in that it is one of the largest of its kind and the results are contrary to the received wisdom about chelation. Instead of noting this, however, what is presented in editorials is a watering down and misrepresentation of the study's findings.

That the body of research on chelation is thin is more reason to be open-minded about its possible effects since even when there is a "mountain of evidence" it hasn't always been enough to insure clarity on an issue. Given such examples one would think medical editors would be more humble and circumspect in their comments. The issue here I'm concerned with isn't chelation but the pattern of behavior and attitudes among medical practitioners that undermine the scientific process in their desire to promote prior unsubstantiated cherished beliefs.

Cvrai,

I was not talking about statistical significance,

Neither was I.

but significance in the body of research on chelation. The TACT study is significant in that it is one of the largest of its kind and the results are contrary to the received wisdom about chelation.

That really isn't true. Firstly chelation has zero prior plausibility i.e. our understanding of atherogenesis does not suggest that chelation will reverse it; I suppose you could describe that as "received wisdom". Secondly, the available evidence strongly suggests that chelation is not effective in treating CVD. Thirdly the TACT study has a raft of very serious problems, such as shoddy procedures, prefilled forms, failure to train personnel, convicted felons with serious conflicts of interest at some sites... (you did read Orac's OP above, didn't you?), as well as problems like a lack of blinding, and the lack of heparin in the placebo. Its results are underwhelming at best, and do not remotely support the claims made for chelation by its practitioners.

Instead of noting this, however, what is presented in editorials is a watering down and misrepresentation of the study’s findings.

Please give specific examples of this.

That the body of research on chelation is thin is more reason to be open-minded about its possible effects since even when there is a “mountain of evidence” it hasn’t always been enough to insure clarity on an issue.

I didn't say the body of research on chelation is "thin", I wrote of the "tiny amount of poor quality evidence that supports chelation" (I don't consider anecdotal reports to be evidence). There is a moderate amount of evidence that supports the hypothesis that chelation is not effective in CVD - see the review I link to above which concludes:

The overall evidence on EDTA chelation therapy argues against any clinical benefit with respect to cardiovascular disease. The evidence that we were able to find in support of EDTA chelation for cardiovascular disease relies almost entirely on uncontrolled trials and a large body of anecdotal evidence.

Compare the similar review on reduced or modified dietary fat for preventing cardiovascular disease I have referred to before, and that you dismiss as being of “minimal relevance”.

Given such examples one would think medical editors would be more humble and circumspect in their comments.

This is a treatment in widespread use that offers false hope to patients, leads them to spend money unnecessarily, and that has serious risks that clearly outweigh any benefits, even if the TACT study's results are accurate (3.5% reduction in CV risk?). I think that's why medical editors are hostile.

The issue here I’m concerned with isn’t chelation but the pattern of behavior and attitudes among medical practitioners that undermine the scientific process in their desire to promote prior unsubstantiated cherished beliefs.

That's exactly the pattern of behavior I am seeing in you here. You seem willing to embrace the poor quality evidence for chelation, yet unwilling to accept much higher quality evidence for dietary fat modification. Why is that?

I often see complaints in CAM circles about conventional medical practitioners and scientists being dogmatic and closed-minded. Having worked with many of these over the years, I have found the opposite to be true. Most of the doctors and scientists I have worked with are curious and open-minded, willing to look at new ideas and to consider evidence that challenges their beliefs.

In contrast, CAM true believers I have talked to are very often dogmatic and narrow-minded, unwilling to even look at evidence that challenges their beliefs, and ready to embrace conspiracy theories to dismiss anything that doesn't fit their "prior unsubstantiated cherished beliefs".

Firstly chelation has zero prior plausibility i.e. our understanding of atherogenesis does not suggest that chelation will reverse it.

I'd say our understanding of atherogenesis is incomplete. Calcium intake has recently been associated with higher CVD mortality. Chelation it is theorized removes the calcium in atherosclerotic plaques. It looks like a rational theory that deserves to be tested. It's not saying for example that the alignment of the stars is affecting the blood's properties. Saying beforehand it is implausible because it does not conform with the prior model (that has a less than stellar record) is unscientific and narrow-minded.

Please give specific examples of [misrepresentation]

A headline from Fox. I'd suggest that reading that article one might be led to believe the TACT study came out against chelation. It certainly seems that's how the reporter read the accompanying editorial.

I didn’t say the body of research on chelation is “thin”, I wrote of the “tiny amount of poor quality evidence that supports chelation” (I don’t consider anecdotal reports to be evidence). There is a moderate amount of evidence that supports the hypothesis that chelation is not effective in CVD – see the review I link to above

The review you refer to seems to be based on six studies two of which were supportive of chelation. I aver that is hardly a basis for a slamdunk conclusion especially in light of the results of the TACT study.

Compare the similar review on reduced or modified dietary fat for preventing cardiovascular disease I have referred to before, and that you dismiss as being of “minimal relevance”.

You refer to the Hooper et al. study. It is an update on an older review. Compare the two and you'll notice a trend towards less significance. Keeping in mind the past 30 years has been a heyday of dietary fat dogma and it is surprising the evidence isn't weighted even more in favor of the reduction of saturated fats. There are other relatively recent reviews that arrive at a different conclusion from the Hooper study here and here.

You seem willing to embrace the poor quality evidence for chelation, yet unwilling to accept much higher quality evidence for dietary fat modification. Why is that?

Embrace chelation for CVD? No. Give it a chance before shooting it down? Yes.

As for the supposed much higher quality of evidence for dietary fat modification, I'd propose a close look at the entire history makes the medical profession look like a laughingstock for letting it take such a prominent place.

Hall—who you brought up—admits dietary cholesterol plays only a small role. Everyone seems to agree blood cholesterol is much more significant. Yet the rather obvious question of what affects blood cholesterol or how does diet affect blood cholesterol went largely ignored next to the campaign against saturated fat. The result? Trans fats and sugar replace saturated fats in the diet and an obesity and diabetes epidemic.

There were warnings before from researchers that this was dangerous but the "consensus" marginalized them and shut them up and the apparatus in place has continued to enforce conformity to the approved dogma. I dislike seeing researchers being noticeably spooked and apologizing for their results. I dislike the ramifications of publication bias and how it is undermining legitimate research. I dislike how this is all passed off as "science-based" when it most assuredly is not.

The results of the unethical and misbegotten Trial to Asess Chelation Therapy (TACT) are finally revealed, part 2

oracknows — Tue, 12 Mar 2013 09:00:02 +0000

The results of the unethical and misbegotten Trial to Asess Chelation Therapy (TACT) are finally revealed, part 2

With very limited exceptions, chelation therapy is, as I said before in my somewhat Insolent opinion, is pure quackery. The sole exception is for real, documented cases of acute heavy metal poisoning that are known to respond to chelation, such as iron overload due to transfusion, aluminum overload due to hemodialysis, copper toxicity due to Wilson's disease, acute heavy metal toxicity, and a handful of other indications. Basically, chelation therapy involves infusing chemicals that can bind to metal ions and make them easier for the kidneys to excrete. The problem is, there is no good basic science or clinical evidence to suggest that mercury from vaccine causes autism or that heavy metal overload causes atherosclerosis. Unfortunately lack of physiologic mechanism, plausibility, and clinical evidence that it doesn't work hasn't stopped chelation therapy from long ago having become a favored "alternative" medicine therapy that is used for atherosclerotic cardiovascular disease (for which it doesn't work), autism (for which it doesn't work and for which its rationale is based on the false idea that mercury from vaccines caused autism), and for general "detoxification" for what ails you, including autism, cancer, Alzheimer's disease (which Hugh Fudenberg has blamed on the flu vaccine, a claim parroted with Bill Maher, of course!), and just about every ailment under the sun

Despite this extreme implausibility, randomized controlled studies showing that chelation is no better than placebo for cardiovascular disease, a veritable cottage industry of chelation therapy for cardiovascular disease long ago sprang up and, against all evidence, persists, fueled by extravagant claims likening chelation to a "Roto-Rooter for your arteries" and an alternative to angioplasty and coronary artery bypass surgery. The belief that chelating toxic metals out of people can treat cardiovascular disease has no basis in physiology, biology, or pharmacology, but it's a major treatment modality favored by naturopaths and many other "alternative" practitioners. Given the infiltration of quackademic medicine into medical academia, it should not be surprising that its advocates promoted clinical trials of this disproven modality. In the early 2000s, they succeeded in the form of the National Institutes of Health (NIH) Trial to Assess Chelation Therapy (TACT), a five year phase 3 trial begun in 2003 to test office-based, intravenous disodium ethylene-diamine-tetra-acetic acid (Na₂EDTA) as a treatment for coronary artery disease (CAD). A few months ago, I commented extensively why the results of this misbegotten and unethical trial presented at the American Heart Association’s annual meeting in a session on late-breaking clinical trials in the form of two abstracts were not nearly as impressive as they were being spun. Kimball Atwood was just as unimpressed.

Kimball and I were just waiting for the results to be published in a real peer-reviewed journal in order to see what other tidbits are there. Then I learned that Gervasio Lamas, the Principle Investigator of the TACT presented more of the results of the study at the American College of Cardiology Meeting this weekend:

Background: We tested the cardiovascular effect of a high-dose oral multivitamin and mineral supplement as a treatment factor in the NIH-funded Trial to Assess Chelation Therapy (TACT). The factorial design eliminated potential confounding from uncontrolled concomitant use of oral vitamins and minerals in patients receiving EDTA chelation or placebo infusions.

Methods: The TACT vitamin study is a double-blind controlled trial comparing an oral high-dose multivitamin and mineral supplement with placebo. A committee of alternative medicine practitioners designed the active oral therapy for use in conjunction with chelation therapy. 1,708 patients were randomized. Inclusion criteria were age 50 or older, MI >6 months prior, and creatinine < 2.0. The active vitamins were a 28-component mixture. The primary endpoint is a composite of death, MI, stroke, coronary revascularization and hospitalization for angina. The analyses are intent-to-treat. Results: Patients were 65 (IQR 59,72) years old, 18% female, and 9% minority. The qualifying myocardial infarction occurred 4.6 (1.6, 9.2) years prior to enrollment. Patients were followed a median of 55 months. There was a high prevalence of diabetes (31%), of prior coronary revascularizations (83%), and use of aspirin (84%), beta-blockers (72%), and statins (73%). Fasting glucose was 102 mg/dL (92, 121), and low-density lipoprotein 89 mg/dL (67, 115). The effect of vitamin therapy will be assessed, as well as its effect in pre-specified subgroups. The event rate in all 4 factorial cells: active oral vitamins + active EDTA chelation infusions; placebo oral vitamins + active EDTA chelation infusions; active oral vitamins + placebo infusions; and placebo oral vitamins + placebo infusions will be reported and compared.

Conclusion: The intent-to-treat analysis of the vitamin arm of TACT will show whether a very high dose of oral vitamins and minerals reduces the incidence of the composite primary endpoint, and whether the effect, if any, is additive to the effect of intravenous chelation therapy.

So basically, the TACT trial was set up according to a 2 x 2 factorial design:

Chelation plus high oral high dose vitamin and mineral supplement
Chelation placebo plus oral high dose vitamin and mineral supplement
Chelation plus oral high dose vitamin and mineral supplement placebo
Chelation placebo plus oral high dose vitamin and mineral supplement placebo

As I noted before, the regimen was described in detail in a recent publication. The vitamin supplements included doses ranging from 25% to 6,667% of the RDA for various vitamins. For example, the dose of vitamin C was 2,000% of the RDA; thiamin, 6,667%; and vitamin A, 500%. The previous presentation looked at the chelation therapy aspect of the study. This study looks at the oral high dose vitamin and mineral supplement treatments.

Basically, this presentation also looks to me like a technique of presenting what we in the biz like to call the "minimal publishable unit" (also known as the MPU). Instead of presenting the results of all four groups in the first presentation last year, Lamas is spreading out the love among multiple presentations. The first time around, it was the chelation arm and the quality of life results. This time around, it's the vitamin/supplement arm. In and of itself, this isn't anything remarkable or even wrong. It's just playing the game, and far too many clinical investigators do it. In any case, the rationale for the vitamin arm of the trial given in Dr. Lamas' slides consists of (1) the observation that chelation practitioners also use high doses of anti-oxidant vitamins and minerals in conjunction with intravenous chelation and (2) oral vitamins and minerals therefore constituted a potential confounder. The primary composite endpoint of the overall study was time to first occurrence of either death, MI, stroke, coronary revascularization, or hospitalization for angina. Of course, as I discussed last time, this sort of composite endpoint, in which all of these different but related endpoints are lumped together, is problematic, as different confounding factors can be amplified, or, as González et al concluded:

The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.

That same problem still exists and is still worth emphasizing. It's not a problem unique to TACT (many cardiovascular trials use similar composite endpoints), but it is the sort of problem that makes barely statistically significant results, like the results of the chelation therapy arm of TACT, suspect if the trial used to obtain them used a composite endpoint. Lamas' reporting of another MPU from this study is also rather annoying because it allows him to refer to his previous presentation has having definitively demonstrated that the TACT had found a definitive treatment effect due to chelation therapy when in fact what he had found might have been statistically significant but was almost certainly not clinically significant.

Cutting to the chase here, the results of this part of the study, which looked at the vitamin supplement arms of the study, were completely negative. There was no signal. Nada, zip. At five years, the composite endpoint showed 37% of patients int he control group had had cardiac events, while 34% in the vitamin groups had, with a p-value of 0.212, nowhere near statistical significance. Moreover, subgroup analysis of the components of the endpoint showed that none of the individual cardiac events that made up the end point were statistically significantly different. This part of the trial is about as negative as negative could be. Of course, this being the TACT trial, the same problems were operative here, including a high dropout rate (50%) for the high dose vitamin arm. Lamas also noted a high vitamin noncompliance rate, but he didn't say what that noncompliance rate was.

He ended up concluding:

High dose oral vitamins reduced the composite outcome by 11%, which was not statistically significant.
When combined with EDTA chelation the benefit was additive and magnitude was statistically significant.

11% Yes, maybe, but the absolute value is 3%. Here's the graph:

Lamas then shows another subgroup analysis for differences between various characteristics of the groups. All of these subgroup analyses were negative two—all save one, which found that patients who were not on statins showed a better hazard ratio due to high dose vitamins. What does this mean? Probably nothing. The authors checked six different subgroups; it's not too surprising that one of them came up "positive." As clinical investigators know, subgroup analyses are fraught with peril to the results of a study. They frequently turn up "positive" results. It's not clear to me from the presentation whether these were post hoc or prespecified subgroup analyses, either, but the smell lik post hoc analyses.

I found this video rather interesting. It's commentary by E. Magnus Ohman, MD, FACC of Duke University, who notes right off the bat that it's "unusual" to have a 2x2 factorial design trial presented in two separate presentations. He points out that it's a single trial. On the other hand he calls it "intriguing" that there was a statistically significant treatment effect between the placebo-placebo group and the high dose vitamins-chelation group. He points out that chelation is being done and will continue to be done regardless of the results of this trial and then opines that there "may be something to this." He even says "it's not wrong."

Well, not really. There are so many problems with this trial that a small effect that is weakly statistically (p=0.16; prespecified p-value required for statistical significance, 0.036 in the original trial—see my original discussion) that its results should be taken with a huge grain of salt. One thing's for sure, there's no benefit to the vitamins. Let's just put the results in context. First, consider these results in the context of what is claimed for chelation therapy. As I described a few months ago, giving lots of examples before, it goes beyond a weakly statistically significant improvement in a composite endpoint. No, quacks claim that chelation therapy can replace angioplasty, stenting, and coronary artery bypass, melting away atherosclerotic plaques, cleaning them out like a "Roto Rooter for your coronary arteries." Even the most generous interpretation of this trial would concede that the benefits of chelation therapy, if they exist, are minimal. Even Dr. Lamas himself concedes that, stating that his study "do not support the use of high-dose vitamin and mineral therapy as an adjunct to optimal evidence-based medical therapy in patients with prior myocardial infarction." No kidding.

I think I can speculate now about why the results were presented in three separate presentations, two at the AHA meeting and one at the ACC meeting, instead of presenting the study as one presentation. Think about it. If the study were presented as a single study, it would be unrelentingly negative, except for one composite endpoint and then only in diabetic patients. If all the results were aggregated together into one presentation, as they should have been, Lamas would have been forced to state in the same presentation that chelation doesn't work except maybe in diabetics (in which the effect is still small and could be due to confounders), that it doesn't improve quality of life, and now that the vitamin component of the therapy is useless. Having them as separate studies allows advocates to point to the positive part of the study as a separate presentation and ignore the other two parts of the trial. Is it cynical of me to say so? Perhaps. The other explanation is that Lamas wanted to maximize the number of presentations by presenting only MPUs, which, while lots of investigators do it, doesn't exactly reflect well on those who do.

oracknows Tue, 03/12/2013 - 05:00

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It's amazing that this trial ever happened. Unfortunately, it looks like it's going to be milked for all its worth to justify chelation therapy as a treatment for heart disease.

How do studies like this get funded?

Any bets on how long it takes before Not-A-Doctor Gokhale shows up to shill his book?

vitamin A, 500%

Clearly the chelation flushes out the excess vitamin A and prevents hypervitaminosis, which is why they combine the two treatments.

@Ken

Clearly the chelation flushes out the excess vitamin A and prevents hypervitaminosis, which is why they combine the two treatments.

A similar thought crossed my mind. Probably why they "only" go to 500% with the vitamin A, instead of into the thousands, as with the water-soluble ones.

Most clinical trials are done to debunk or approve an agenda by the sponsoring organization. I from first hand experience, used EDTA in an IV form due to a MI. It saved my life and cleared my arteries. Per the failing of a treadmill test and other tests my arteries were partly blocked. To make a long story short, all the so-called trials will never debunk my actual experience. I noted the changes that were taking place in my body and the amount of exercise I was able to do at a progressively high rate. I was not on any supplemental mega-doses of vitamins/minerals. Every tenth treatment was a trace mineral IV to replace the minerals lost. I did forty treatments which was the protocol at the time. That was 13 years ago and today my blood pressure is down from 155/90 to 115/65. I have an educational and science background. So unless you have walked in my shoes be less judgmental from looking in from the outside. For all the people out there making a "fast buck" to those I have no respect. But even in a good steak you find a bone. Just spit it out and enjoy the meat.

Of course, you know your anecdote is worthless as evidence. Get a filet mignon next time.

@ Gary:

You have no actual evidence that the results were actually due to the chelation. So yes, the clinical trial results do completely debunk that argument.

all the so-called trials will never debunk my actual experience

I have an educational and science background.

I guess your 'science background' didn't work out so well. You relayed an anecdote. You, being a fallible human like the rest of us, are completely unable to determine whether or not it was in fact the chelation that was responsible for your improvement, and whether it would work for others.

Most clinical trials are done to debunk or approve an agenda by the sponsoring organization.

Are you seriously claiming that this study was designed to discredit chelation? I think you should do some reading on who is actually behind this trial.

"And away go plaque deposits, down the drain
Roto-rooter!"

You just gotta listen to your body.*

*I stopped listening to my body, it just kept demanding Wendy's triple cheeseburgers and half-gallon tubs of rum raisin ice cream.

I wonder if our 'Gary P from AZ' is connected to Garry Gordon, noted chelation nut and homeopath, who runs a quack institute in AZ.

@Gary

And 13 years ago I got a stent--it probably saved my life. The thing is, there is actual evidence to my claim, and I qualified my claim, just to be on the safe side.

I don't have a huge science background (enough to know what the scientific method is and how it works), but I do know the basics of critical thinking, which keeps my skeptical eye sharp and helps me decide who and what to read.

The results of the unethical and misbegotten Trial to Asess Chelation Therapy (TACT) are finally revealed

oracknows — Mon, 05 Nov 2012 02:00:40 +0000

The results of the unethical and misbegotten Trial to Asess Chelation Therapy (TACT) are finally revealed

Chelation therapy, in my somewhat Insolent opinion, is pure quackery. Unfortunately, it's also one of the most common quackeries out there, used by a wide variety of practitioners for a wide variety of ailments blamed on "heavy metal toxicity." Chelation therapy involves using chemicals that can bind to the metal ions and allow them to be excreted by the kidneys is standard therapy for certain types of acute heavy metal poisoning, such as iron overload due to transfusion, aluminum overload due to hemodialysis, copper toxicity due to Wilson's disease, acute heavy metal toxicity, and a handful of other indications.

My personal interest in chelation therapy developed out of its use by quacks who blamed autism on the mercury-containing thimerosal preservative that used to be in many childhood vaccines until 2001 but has since all but disappeared from such vaccines except for one vaccine (the flu vaccine, for which a thimerosal-free alternative is available) and in trace amounts in some other vaccines. Mercury became a convenient bogeyman to add to the list of "toxins" antivaccinationists hype in vaccines. In fact, I've been writing about the pseudoscience behind the claim that mercury in vaccines is a cause of autism since nearly the very beginning of this blog, and I've periodically written about such things ever since, in particular the bad science of Mark and David Geier, whose idea that chemical castration of children with Lupron "works" against "mercury-induced" autism is based on a chemically ridiculous idea that somehow testosterone binds mercury and makes it harder to chelate. Unfortunately, this particular autism quackery has real consequences and has been responsible for the death of a child.

Chelation isn't just for autism, though. It's the quackery that quacks love for almost anything. Despite many practitioners advertising it for autism, cancer, Alzheimer's disease (which Hugh Fudenberg has blamed on the flu vaccine, a claim parroted with Bill Maher, of course!), and just about every ailment under the sun, it's easy to forget that the original use for chelation therapy promoted by "alternative medicine" practitioners was for cardiovascular disease. When it is used for coronary artery disease or autism, on a strictly stoichiometric and pharmacological basis, it is extremely implausible.Moreover, it is not without potential complications, including renal damage and cardiac arrhythmias due to sudden drops in calcium levels. Such arrhythmias can and have led to death in children, and in adults complications such as renal failure and death.

The belief that chelating toxic metals out of people can treat cardiovascular disease has no basis in physiology, biology, or pharmacology, but it's a major treatment modality favored by naturopaths and many other "alternative" practitioners. Given the infiltration of quackademic medicine into medical academia, it should not be surprising that its advocates promoted clinical trials of this disproven modality. In the early 2000s, they succeeded in the form of the National Institutes of Health (NIH) Trial to Assess Chelation Therapy (TACT), a five year phase 3 trial begun in 2003 to test office-based, intravenous disodium ethylene-diamine-tetra-acetic acid (Na₂EDTA) as a treatment for coronary artery disease (CAD). A while back, I learned that the results of this trial would finally be revealed on Sunday (i.e., yesterday) at the American Heart Association's annual meeting in a session on late-breaking clinical trials in the form of two abstracts:

Results of the Trial to Assess Chelation Therapy
Quality of Life Outcomes in the Trial to Assess Chelation Therapy (TACT)

The story was embargoed until last night, but now the embargo is lifted and we can write about it freely, thanks to press releases and reported results of the trial. I expect that the results are—shall we say?—disappointing to chelationists. Certainly if this were a conventional medical therapy it would not be viewed as a particularly favorable trial. However, there are enough equivocal findings that the alt-med websites will soon be touting this study as ironclad evidence that chelation therapy works as well as bypass surgery. I guarantee it. In fact, I wouldn't be surprised if such articles appear at the same time as this post. Chelationists have access to press information too and tend not to be as fastidious as us in honoring press embargoes.

The story of how this $30 million trial is long and depressing and was documented ably and in extreme detail in 2008 by my good bud Kimball Atwood, along with Wally Sampson, Elizabeth Woeckner and Robert Baratz, in an article for the Medscape Journal of Medicine entitled Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned. In it, Atwood et al documented the long and dubious history of TACT, how it came about through the political influence far more than scientific merit (of which it has virtually none), and how the investigators are utterly unqualified to carry out such a large multicenter trial, concluding that the TACT is "pointless, dangerous, unethical, and wasteful." It's worth reading the article in full detail, as well as other posts by Kimball Atwood, not to mention a post or two by yours truly. In addition, you should check out R. W. Donnell's Magical Mystery Tour of NCCAM Chelation Study Sites, Part I, Part II, Part III, Part IV, Part V, Part VI, and Part VII. Seriously. As Dr. Donnell points out, only 12 of the 110 TACT study sites were academic medical centers. Many of the study sites were highly dubious clinics touting highly dubious therapies, including heavy metal analysis for chronic fatigue, intravenous infusions of vitamins and minerals (I could never figure out how infusing minerals could be reconciled with chelation therapy to remove minerals, but that's just me), antiaging therapies, assessment of hormone status by saliva testing, and much more. Dr. Donnell also points out that the blinding of the study groups to local investigators was likely to have been faulty. So right off the bat, this study was dubious for so many reasons, not the least of which was that some of its site investigators were felons, a problem blithely dismissed by the NIH as being in essence irrelevant to whether the study could be done safely.

Efficacy? It's a part of my science-based medicine fantasy.

Let's take a look at the results of TACT, starting with the main outcome measures first, and then we'll move on to the presentation describing quality of life (QOL) measures. The first presentation is by Gervasio Lamas, MD, a professor of clinical medicine at the Columbia University Division of Cardiology and now Chairman of Medicine at Mount Sinai Medical Center. and was entitled The Trial To Assess Chelation Therapy (TACT): Chelation-Placebo Comparison. One notes right away that the study was funded by the National Center for Complementary and Alternative Medicine (NCCAM, grant U01AT001156) and the National Heart, Lung and Blood Institute (NHLBI, U01HL092607). What's interesting here is that the study was originally funded by NCCAM and then taken over by NHLBI later. NCCAM seems to be almost embarrassed by it, however. For example, the director of NCCAM, Dr. Josephine Briggs, has a tendency to be very quick to dismiss TACT as no longer within NCCAM's purview. She is clearly embarrassed by our question and also dismissed it as having come into existence before she took over as director at NCCAM. The second thing I noticed was that this was funded under the NIH U01 mechanism. This mechanism is designed to fund multi-institution collaborations to "discrete, specified, circumscribed projects to be performed by investigator(s) in an area representing their specific interests and competencies." In practice, what I gather from more senior investigators is that U01 grants are less like R01 grants and more like contracts (more specifically, they are cooperative agreements) to carry out specific projects. As such, they appear to be a bit more amenable to political pressures to be granted—or at least were.

The trial was a 2 x 2 factorial design that looked at:

Chelation plus high oral high dose vitamin and mineral supplement
Chelation placebo plus oral high dose vitamin and mineral supplement
Chelation plus oral high dose vitamin and mineral supplement placebo
Chelation placebo plus oral high dose vitamin and mineral supplement placebo

The regimen was also quite rigorous and is described in detail in a recent publication. One notes that the vitamin supplements included doses ranging from 25% to 6,667% of the RDA for these vitamins. For instance, the dose of vitamin C was 2,000% of the RDA; thiamin, 6,667%; and vitamin A, 500%. There were a total of 40 infusions that took three hours each. Thirty of these were administered weekly, followed by ten "maintenance" infusions administered two to eight weeks apart. Now let's look at the nitty-gritty, followed by the results. First up, the inclusion criteria were:

Age 50 or older
MI > 6 months prior
Creatinine <2.0 mg/dL
No coronary or carotid revascularization within 6 months
No active heart failure or heart failure hospitalization within 6 months
Able to tolerate 500cc infusions weekly
No cigarette smoking within 3 months
Informed consent

The exclusion criteria were:

Chelation therapy within 5 years
Allergy to any study drug
Coronary or carotid revascularization within 6 months
Planned revascularization
Symptomatic or clinically evident heart failure
Heart failure hospitalization within 6 months
Blood pressure > 160/100
No venous access
Serum creatinine > 2.0 mg/dL
Platelet count <100000/mm3
Cigarette smoking within the last 3 months
Liver disease or ALT or AST >2.0 times the upper limit of normal
Diseases of copper, iron, or calcium metabolism
Inability to tolerate 500 mL of fluids weekly
Inability to keep to study schedules
Medical condition likely to affect patient survival within 4 years
Women of child-bearing potential

The placebo infusion consisted of 500 mL normal saline and 1.2% dextrose, while the chelation infusion consisted of:

disodium EDTA, 3 grams, adjusted downward based on eGFR,
ascorbic acid, 7 grams
magnesium chloride, 2 grams
potassium chloride, 2 mEq
sodium bicarbonate, 840 mg
pantothenic acid, thiamine, pyridoxine,
procaine, 100 mg
unfractionated heparin, 2500 U
sterile water to 500 mL

I find it very interesting that the investigators included procaine (a product of evil big pharma) in the chelation mixture. Yes, I know that disodium EDTA is also a product of the evil big pharma, but one can't very well do chelation therapy without the chelating agent, can one? In any case, procaine is actually Novocaine and is a topical anesthetic. Its inclusion makes me wonder how much the chelation concoction being tested in TACT hurts as it is injected, as we usually don't add local anesthetics to infusions unless the infusion causes significant pain at the injection site. Could this also contribute to the ability of patients to know if they're getting the "real" drug (and, yes, disodium EDTA is a drug)? One wonders, one does.

One last piece needs to be put into place, and that's to let you know the outcomes that were tested in TACT. The primary endpoint is a composite of death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. In other words, investigators took all of these endpoints and added them together. The significance of this design will become clear in a moment, after I reveal the results. Another important point was that the original plan was to randomize 2,372 patients with a one year followup, a design that was estimated to have 85% power to detect a 25% difference. However, in 2009, due to low enrollment (more on that later), it was pointed out that "blinded investigators asked for a reduction of total sample size to 1,700, with a compensatory increase in follow-up to maintain same unconditional power." I find it rather interesting that the word "blinded" is used, instead of just saying that the investigators asked for a decrease in number and a longer followup time in order to try to compensate for low accrual. The implication to me is that there were some investigators who were not blinded. Whether I'm reading too much into this or not, I don't know, but it sounds odd. In any case, the request was approved.

So, on to the results. The result being touted by the investigators is described in the press release:

Heart attack patients given weekly infusions of chemicals used for chelation therapy had fewer cardiovascular events than those who received identical appearing placebo infusions, according to late-breaking clinical trial results presented at the American Heart Association’s Scientific Sessions 2012.

In the multicenter, double-blind efficacy trial, Trial to Assess Chelation Therapy (TACT),1,708 heart attack patients were randomized to receive 40 infusions of a 500 mL chelation solution or a placebo infusion, with a second randomization to an oral vitamin and mineral regimen or an oral placebo. The chelation solution contained three grams of the synthetic amino acid ethylene diamine tetra-acetic (EDTA), seven grams of vitamin C, B-vitamins, electrolytes, a local anesthetic and heparin, an anti-clotting drug. The placebo infusion was salt water and a small amount of sugar.

Researchers found that patients receiving the chelation solution had fewer serious cardiovascular events than the control group (26 percent vs. 30 percent). Cardiovascular events were defined as death, heart attack, stroke, coronary revascularization and hospitalization for angina.

Although participants with diabetes appeared to have a particular benefit from the infusions, the study team cautioned that subgroup analyses can be unreliable and need to be reproduced.

There's the spin. Let's look at the results. The primary endpoint (i.e., the aggregated serious cardiovascular events) did indeed show a modest difference, namely 30% of placebo subjects versus 26.5% of the EDTA chelation subjects (hazard ratio 0.82 for chelation). However, the result is just barely statistically significant, p = 0.035, with the 99% confidence interval for the hazard ratio ranging from 0.69 to 0.99. Note that the predetermined level for statistical significance for purposes of this study was 0.036. More importantly, if you look at the individual endpoints that make up that aggregate, there was no statistically significant difference in death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. Subgroup analysis (always a questionable analysis that requires replication, even when preplanned, as in TACT) purported to show a much greater benefit for diabetics, with a hazard ratio of 0.61 (p=0.002), while patients without diabetes showed no statistically significant difference in any of the outcome measures, including the aggregated total bad outcomes (I like that term better).

There were some problems, as you might imagine. First off, only 65% of subjects finished all infusions, with only 76% finishing at least 30. That's a high drop-out rate, and is likely largely due to just how grueling it is to have to undergo weekly three hour infusions for well over six months, followed by several more months of less frequent infusions. Moreover, 17% withdrew consent, resulting in missing data. I'm not sure how the investigators tried to correct for this (there are standard ways to do it), but these issues are serious. They might not be so serious if there had been a much more convincing treatment effect, but when you get equivocal results such as this such issues loom much larger. Indeed, critics have correctly pointed this out, as in this AP report:

Other experts questioned the results, especially because 60 more people in the group getting dummy infusions withdrew from the study than in the group getting chelation. Usually, more people in a treatment group drop out because of side effects, said Dr. Christie Ballantyne, a Baylor College of Medicine heart specialist. To find the opposite is "a red flag" that suggests those who got dummy treatments found that out and decided to drop out.

"There's something funky going on here," Ballantyne said. "It raises questions about study conduct," especially since a difference of one or two people or complications could have nullified the small overall benefit researchers reported.

Dr. Clyde Yancy, a Northwestern University cardiologist and a former Heart Association president, agreed.

"It's funny business," he said. "I've never seen a study in which one in five people withdrew consent."

Funny business is an understatement. A complete, unabashed fiasco would be a better description. Or maybe a total and complete waste of taxpayer money. Or perhaps an unethical sham of a trial, perhaps? Whatever you want to call TACT, this concern is quite consistent with worries expressed over six years ago by Dr. R. W. Donnell about the adequacy of the blinding of the trial. In light of such concerns, the differential drop-out rate between the two groups makes a lot more sense. Too bad that Dr. Lamias apparently didn't see fit to include the relevant information in his press release or in his slide set.

Finally, no study would be complete without a consideration of adverse events. After all, in determining whether a therapy is worth pursuing, it is important to weigh its efficaciousness versus its safety. Overall, 79 adverse events were observed forcing discontinuation of infusions. Reasons included: reaching an endpoint; heart failure; other cardiac issues; GI problems; hematological problems; and a variety of other problems. Unfortunately, the presentation slides did not break down how many of these 79 adverse events occurred for patients in the treatment group versus patients from the placebo groups. In fact, given that there were four groups, these adverse events needed to be broken down into four groups but were not. There were a total of four unexpected severe adverse events possibly or definitely related to study therapy, two in the placebo group with one death and two in the treatment group, with one death. Kimball Atwood discussed some of the serious adverse events before in detail. It's not entirely clear that these deaths didn't have a lot to do with the incompetence of some of the investigators at the local sites where these patients were treated.

I will be awaiting the full publication, in which (hopefully) more will be revealed about these two deaths. In the meantime, it is clear to me that, even if these results are valid and there is a small benefit to chelation therapy, it's a long run for a risky short slide.

Quality of life? We don't need no steekin' quality of life?

Still, even though the results are so unconvincing that the study investigators concluded that TACT "does not constitute evidence to recommend the clinical application of chelation therapy" and that (of course!) "additional research will be needed to confirm or refute our results and explore possible mechanisms of therapy" while also saying TACT showed "some evidence of a potentially important treatment signal in post-MI patients already on evidence-based therapy," maybe the therapy does something for quality of life. It's possible, albeit highly implausible. So in parallel, QOL outcomes were measured and presented as a second abstract at AHA presented by Daniel B. Mark, MD, MPH.

Several QOL tools were administered to participants in TACT. These included:

DASI: A cardiac-related functional status tool that ranges from 0-58 and reflects the ability of patients to do physical activities without difficulty or assistance in 12 domains
MHI-5: A tool that measures psychological well-being, including both
depression and anxiety. Investigators normalized scores to 50±10, with clinically significant difference being >2.5 points.
Other measures: SAQ (frequency, stability, QOL), SF-36, EQ-5D

In brief, 911 (53%) of the 1,708 main TACT subjects were randomly selected for the QOL substudy, with structured interviews at baseline, 6 months, 12 months, and 24 months. Let me tell you, though, that this study will be much easier to discuss than the main TACT trial for one very simple reason. There were no statistically significant differences in QOL outcomes measured for any of the assessment tools used at any of the time points examined.

So what do you do when your study is completely negative? Easy! You do subgroup analysis, and that's what Mark et al did. Well, actually, these subgroup analyses were prespecified; so it's basically legitimate. Even so, they couldn't find much. All they could find is that patients with angina symptoms at baseline showed a modest treatment effect in favor of chelation therapy at one year, but at none of the other time points. A good rule of thumb is that for repeated measures, seeing an effect at only one time point is strongly suggestive that the difference for that time point is spurious and not real; so there isn't much to say about this other than that this was about as close to a completely negative study as one might imagine, and even the press release had to acknowledge that:

“We didn’t see any effect on the quality of life of chelation therapy patients,” said Daniel B. Mark, M.D., M.P.H., lead author of the sub-study and professor of medicine, director of outcomes research at Duke University Medical Center and Duke Clinical Research Institute in Durham, N.C. “Patients weren’t any worse, but they weren’t any better.

One of the tools used to measure quality of life was the Duke Activity Status Index, DASI, to measure patients’ ability to complete daily tasks. The lowest score of 0 means the patient couldn’t do any chores associated with their own care such as feeding, toileting and dressing themselves. The highest score of 48 would be achieved by a professional athlete, Mark said.

At the beginning of the study, patients taking chelation therapy had a score of 24.6 and after two years it went up to 27.1. Those on placebo, dummy infusions that contained no medicine, had a baseline score of 23.5 that went up to 25.1. The small difference between chelation and placebo wasn’t significant enough to show a notable impact on how patients functioned in their daily lives.

The results were similar when researchers used the SF-36, the Short Form Health Survey, which assesses mental wellbeing or stress. After two years of chelation or placebo, patients reported similar scores.

“We thought it might make people feel better, but we didn’t see that consistently enough,” Mark said.

No, Dr. Mark didn't see it at all, just as the trial investigators apparently didn't see Edzard Ernst's criticisms of their trial design when they cited his review article as a source. As Dr. Ernst put it:

The TACT has been criticized as being "unethical, dangerous, pointless and wasteful." Yet, Lamas et al inform us that it went ahead with “reduced sample size” and that “TACT has finished enrolment.” From my perspective, the most puzzling part of the article of Lamas et al is the following sentence: "EDTA chelation of divalent and trivalent ions has been postulated to produce a favorable effect on atherosclerotic plaque, questionably leading to improvement in endothelial function, reductions in symptoms, and major vascular events." To support this statement, Lamas et al cite my review that shows an “almost total lack of convincing evidence” and concludes that "given the potential of chelation therapy to cause severe adverse effects, this treatment should now be considered obsolete."

Ernst was correct, and the now-revealed results of TACT only serve to confirm that.

The bottom line

When we criticize NCCAM and the infiltration of quackademic medicine into medical academia, we often point to the many pernicious effects that "integrating" pseudoscience with science- and evidence-based medicine has. One of these is the drive to test highly implausible therapies without adequate preclinical evidence, a practice at odds with the Helsinki Declaration's requirement that clinical trials be based on firm basic science in preclinical models. This is problematic enough from an ethical standpoint when the treatment being tested is water (i.e., homeopathy), but when it's an active treatment with real risks, it is completely unethical. That's why I have said on multiple occasions that TACT is completely unethical. Worse, TACT was not funded based on a clinical need, scientific or clinical promise, or scientific merit due to its potential to reveal an important previously unsuspected mechanism of disease or target for treatment. Rather, it came into existence because a pro-quackery legislator, Rep. Dan Burton (R-IN) strong-armed the then-director of NCCAM to green light it. Later, it became such an albatross about NCCAM's neck that NCCAM ceded control to NHBLI and downgraded its involvement to an advisory capacity. Indeed, Dr. Lamas himself seems to indicate that even he didn't expect any positive results from TACT, although I suppose it's possible that he means it was unexpected that this trial was, in essence, a negative trial:

"We have to look carefully at these unexpected results," said Gervasio A. (Tony) Lamas, M.D., lead author of the study and chief of Columbia University Division of Cardiology at Mount Sinai Medical Center in Miami Beach, Fla. "Although not approved by the Food and Drug Administration for treating heart disease, chelation therapy has been used for over 50 years and has generally been believed by conventional medical practitioners and cardiologists to be without value. A definitive answer on chelation therapy will take much additional research. The most exciting part of this study is that there may be an unexpected signal of benefit. We need to understand whether the signal is true, or whether it occurred by chance."

No, the "signal" only comes from having aggregated a bunch of outcomes into one large outcome, and even then this signal, in a study of over 1,700 patients, strained to reach statistical significance. On each and every individual outcome, the "signal" doesn't exist!

Let's step back a moment an look at this. In the case of TACT, the result of the "integration" of quackery with scientific medicine has been to spend $30 million on a trial conducted at highly dubious CAM and "integrative" medicine clinics whose practitioners were completely unqualified to carry it out. This expenditure of scarce research dollars has resulted in a primary finding that is at best equivocal and at worst completely negative, and a secondary finding that is completely negative. Even if this study's results are taken at face value, we can say that chelation therapy for coronary artery disease does not increase survival, obviate the need for angioplasty or CABG surgery (a prime claim frequently made by chelationists), or even decrease the severity of patients' angina symptoms or increase their tolerance for physical activity. It is worthless. Actually, it's worse than worthless, because it's expensive, arduous, and, even if we took TACT's reported results at face value, promises minimal benefit.

I am not condemning this trial because it was negative. Sometimes—often, in fact—clinical trials fail to find a benefit from the experimental treatment. There's nothing wrong with that. However, such clinical trials are based on a sound preclinical evidence base of basic science and animal experimentation that indicates scientific plausibility and a reasonable likelihood that the treatment would be efficacious in humans. TACT had none of these things. Indeed, there was an existing preclinical and clinical evidence base that gave every indication that chelation therapy shouldn't work.

The acceptance of chelation among CAM practitioners is also as good an exapmle of the CAM double standard as I've ever seen. Imagine, if you will, if big pharma produced a treatment like chelation therapy that had no good preclinical evidence suggesting its efficacy and several existing clinical trials suggesting that it does no better than placebo for cardiovascular disease. Imagine that big pharma tried to get FDA approval to market its chelation therapy for cardiovascular disease. Imagine how CAM practitioners would react. Now look for how they react to this trial. I can predict it. (Not that it's hard or anything.) They'll make excuses. They'll cherry pick the one seemingly promising result. They'll claim that there was something wrong with the protocol or that the wrong chelating agent was used. They'll demand more studies. In other words, they won't simply admit that their therapy doesn't work and move on.

In fact, I'm already thinking of things that quacks will say about this trial to try to excuse its failure and justify continuing to use chelation. One of them has already been used. In fact, it's right there in the AP story:

The study's leader, Dr. Gervasio Lamas of Mount Sinai Medical Center in Miami, said: "The trial needs to be taken for what it is — a step towards future investigation."

Yes, it's the "more study is needed" gambit. In these cases, unfortunately, the problem is that more study is always needed, regardless of how negative the study.

oracknows Sun, 11/04/2012 - 21:00

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