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.