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We Finally Learn From TACT2 What We Should Have Known Two Decades Ago: Chelation Therapy Doesn't Work For Heart Disease

In the days leading up to my starting to write today's post, I thought that I'd just write a followup to last week's post about "turbo cancers" supposedly caused by COVID-19 vaccines, mainly because there are as yet two truly awful articles supposedly supporting this antivax claim that I have yet to deal with. However, as I was perusing my usual sources for blogging topics, I realized that I've already written about "turbo cancer" twice in a row, but more importantly I came across articles that would allow me to "close the loop," so to speak on a topic that was a frequent topic of discussion on this blog going back to its very beginning, as well as on my not-so-super-secret other blog going way, way back. That topic is the quackery known as chelation therapy for cardiovascular disease (particularly coronary artery disease) and how the evidence-based medicine (EBM) model had led the NIH to spend $30 million on an unethical study (Trial to Assess Chelation Therapy, or TACT) to assess whether chelation therapy actually works. The result was an at best equivocal study that was widely touted by quacks after its results were reported in 2012 as proof of the efficacy and safety of the treatment, even though it only showed a benefit using a composite endpoint—there was no statistically significant difference in any of the endpoints that made up the composite endpoint—and then only in diabetic patients.

Given its $30 million price tag, we at SBM considered TACT to be arguably the most egregious example of the single biggest blindspot in EBM, namely the failure to consider prior probability in deciding whether a treatment has sufficient preclinical evidence to justify a large phase 3 clinical trial. It was pure quackademic medicine, in which, thanks to that blindspot in EBM, quackery is treated seriously enough to merit a study costing tens of millions of dollars that could have been better used to study treatments with an actual likelihood of working. Moreover, as predicted, the results of TACT didn't change "integrative medicine" practice. As I wrote at the time, if "integrative medicine" specialists, naturopaths, and the like actually believed the conclusions of TACT, they should have immediately stopped treating their nondiabetic patients with heart disease using chelation therapy. After all, TACT clearly showed zero difference between chelation and placebo in cardiovascular outcomes, even using the Frankenendpoint chosen (the composite endpoint). They did not. Instead, chelation advocates used the results of TACT to persuade the NIH to fund to the tune of $37 million what I called the "Son of TACT" but what ended up being called TACT2, the original TACT now being referred to as TACT1. Its aim was to study the use of chelation therapy in diabetic patients with heart disease. It was the reporting of the results of TACT2 at the recent American College of Cardiology meeting earlier this month that chelation therapy that made me immediately realize that I was tired of writing about turbo cancer and needed a brake. Spoiler alert: TACT2 was a completely negative clinical trial, which is why I wanted to write this post.

So basically, the NIH spent $67 million on two trials that never needed to be done to come up with a result 21 years after the first TACT trial started that we had been predicting all along. What really made me want to write about this again, though, was the reaction of a certain cardiologist and EBM maven, Dr. John Mandrola, who posted to Sensible Medicine an article Chelation Did Not Work But Science Did, with the tagline, "When the TACT 2 trial failed to confirm TACT 1, the winner was science."

Nope. In fact, TACT2 was anything but a win for science, and reactions from EBM mavens like the one above are part of what is so infuriating about the current EBM model. Let me explain why. I'll start by discussing chelation and its history, move on to discussing TACT1, and then finish by discussing TACT2, all while interspersing my usual commentary about how credulous some doctors can be.

TACT1: The genesis of an unethical and unnecessary clinical trial

Perhaps the most definitive description of why TACT1 was unnecessary and unethical and never should have been done, much less at a cost of $30 million was written by former regular here at SBM, Dr. Kimball Atwood, along with Elizabeth Woeckner, Dr. Robert Baratz, and the late great Dr. Wally Sampson, in Medscape in a 2008 article entitled Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned. It's an article worth reading in its entirety, but what is interesting is the history of chelation therapy and how the trial came to be, all of which I'm pretty sure that Dr. Mandrola and those thinking similarly about chelation therapy are unaware of. It's a history that goes back to the 1950s—nearly 70 years ago.

First, though, what is the rationale for chelation therapy to treat atherosclerotic cardiovascular disease? The rationale is simple enough. Mature atherosclerotic plaques often have calcium in them; so it was hypothesized that "decalcification" of these plaques could reduce them in size, improve blood flow, and decrease the complications that result from decreased blood flow due to such plaques. However, as Atwood et al noted about coronary artery disease (CAD), peripheral vascular disease (PVD), and cerebrovascular disease (CVD):

Beginning in 1956, a few small, uncontrolled case series reported that IV Na2EDTA seemed to have striking, beneficial effects on CAD, PVD, and cerebrovascular disease.[32,50,51,52,53] By 1963 it became clear that those reports, which were based primarily on subjective outcomes, had been wrong. When followed for more than a few months, subjects with CAD had rates of death and MI similar to those expected for untreated patients at that time.[54] Two small series of subjects with intermittent claudication had also shown no evidence of improvement.[54,55] Several autopsies from various series had revealed no evidence of decalcification of plaques or reduction of plaque size. Within a couple of years, case series of IV Na2EDTA for cardiovascular disease no longer appeared in the academic medical literature.

Note that references #54 and #55 cited by Atwood et al. Are from 1963 and 1964, roughly 60 years ago. So what happened? Why did chelation therapy for CAD, PVD, and CVD not only persist but actually make a comeback a couple of decades later, even though evidence as it existed in the early 1960s would seem to have been enough to bury it for good as ineffective and potentially dangerous, the key risk coming from the possibility that chelation could lower the concentration of calcium ion in the blood to a dangerously low level that could cause fatal arrhythmias? It wasn't, though. A small band of enthusiasts who still believed that chelation not only worked but worked nearly miraculously kept offering it in their offices, amending the protocol to include not just disodium EDTA, but magnesium, vitamins, and minerals, followed by monthly "maintenance" infusions, advertising the concoction as a "chemical Roto-Rooter" or a "chemical endarterectomy." (An endarterectomy is a surgical procedure that removes atherosclerotic plaques from arteries to improve blood flow. It's used primarily for the carotid arteries in order to prevent strokes in patients with a high degree of narrowing due to atherosclerotic plaques.)

As is often the case with treatments like this, "indication creep" lead "alternative medicine" practitioners to tout chelation therapy as a panacea, a near cure-all, for conditions as unrelated and diverse as disparate as multiple sclerosis, schizophrenia, autism, cancer, peptic ulcer, back pain, and chronic obstructive pulmonary disease. Indeed, my first encounters with chelation therapy as a skeptic of alternative medicine were in the context of its use to treat "vaccine-induced autism." Sadly, one of my strongest memories from that period long ago included a tragic case in 2005 in which a 5-year-old autistic boy named Abubakar Tariq Nadama died of a fatal arrhythmia while being treated with chelation therapy for autism. The quack, an otolaryngologist named Dr. Roy Kerry, was ultimately charged with involuntary manslaughter, endangering the welfare of children and reckless endangerment. Outrageously, the prosecutor dropped all charges based on a rather technical point about which form of EDTA was used. What penalty did Dr. Kerry face? In 2009, he signed a consent agreement under which his medical license was suspended for six months, after which he had to serve probation for 2-1/2 years. The agreement also barred him from chelating anyone under age 18 and required him to undergo a fitness-to-practice evaluation and have his practice monitored by another doctor during his probation. That's it.

Of course, one might concede that of course it's quackery to treat autism with chelation therapy given that there's no evidence that "heavy metal" toxicity has anything to do with the development of autism while still believing that chelation might prove beneficial treating CVD, even though, similarly, there's never been good evidence that elevated levels of calcium, lead, etc., contribute to the development of atherosclerotic plaques or, more importantly, that chelating heavy metals leads to their reversal. So let's get back to the genesis of TACT1.

Atwood et al go on to describe the formation of the American College for Advancement in Medicine (ACAM), which advocated for various alternative medicine treatments, in particular laetrile, to be "integrated" into medical practice, whose doctors had a large role in developing the "evidence base" (if you can call it that) used to justify TACT to NIH:

Reports of uncontrolled series of IV Na2EDTA for cardiovascular and other diseases began to reappear in about 1980. Unlike the original reports, these were written exclusively by advocates, all members of the AAMP/ACAM, and published, with 1 or 2 exceptions, in little-known, nonrefereed journals. Several articles reported sample sizes in the hundreds or thousands. Each series reported dramatic improvements in 80% to 90% of subjects.[34,57,88,89]

Complications, if mentioned, were described as minor. Rates of death from any cause, if mentioned, were implausibly low. For example, in a report of 2870 subjects, most of whom were said to have CAD (844 subjects), PVD (1130 subjects), or cerebrovascular disease (504 subjects), followed in Brazil for a 2-year period in the early 1980s, the authors reported 7 deaths; 2 were in the CAD group.[90,91] In a subsequent report, the same authors wrote that when chelation had been "administered according to the ACAM protocol," there hadn't been "a single reported incident of renal failure or death since 1960.[92]" As discussed in Part III of this article, the claim was false and the authors had reason to know it.[18,93,94] One of those authors, James Carter, is now a TACT co-investigator.[7]

Two reports were "meta-analyses" of the others, reporting more than 20,000 subjects and creating, for their statistical analyses, imaginary control groups "defined to have no improvement in cardiovascular capability.[95,96]" The first author of those reports is "prominent expert" L. Terry Chappell, also now a TACT co-investigator.[4,7]

As for the "decalcification" hypothesis that ACAM used to explain why chelation "worked":

As it became clearer that the decalcification theory was no longer taken seriously by medical scientists, chelationists sought new explanations for the putative effects of Na2EDTA, though never relinquishing the old one.[80,100]Several were proposed, among them platelet function inhibition, anticoagulation, lowering of serum lipids, and calcium channel blockade. The most popular one, which persists, was based on the removal of toxic heavy metals. Through the removal of iron, mercury, aluminum, lead, and other metals that, according to advocates, are toxic even at the miniscule levels found in most people, the panacea effects of chelation are explained.

So how did TACT1 come about? Dear reader, here's where a politician familiar to longtime readers enters the picture, Rep. Dan Burton (R-Indiana). You might remember him for being a longtime chair of the House Oversight Committee, where, back in the 1990s and early 2000s, in the service of his belief that vaccines had caused his grandchild to become autistic, would frequently hold hearings in which he would torment CDC and FDA officials about bogus science supposedly linking vaccines to autism. Guess what? It was Rep. Burton who pressured the NIH to fund TACT:

In March 1999, ACAM presidents L. Terry Chappell and Ted Rozema shilled for chelation at a hearing of the House Committee on Government Reform, chaired by a powerful "health freedom" ally and veteran of the Laetrile wars, Rep. Dan Burton (R-IN).[41,167,168] NHLBI Director Claude Lenfant, whom Burton had summoned, was present. Burton criticized the NHLBI for "never funding any research into chelation therapy"; he criticized the National Library of Medicine for not listing the Journal of Advancement in Medicineon MEDLINE; he criticized the FTC for "launch[ing] an attack on the free flow of information from a non-profit professional medical association.[41]"

Burton scolded Director Lenfant for his institute's "bias" against chelation and other "alternative" methods and declared that he, Burton, would personally bring the purportedly large number of applications for chelation research "right to your office and lay them on your desk.[41]" Dr. Lenfant replied that there had been only 1 proposal to the NHLBI for a clinical study of chelation in the previous 30 years.

Ultimately, in 2001 the NIH (specifically the NHBLI and the then-named National Center for Complementary and Alternative Medicine) wanted to do a randomized controlled trial (RCT) and issued a joint Request for Applications (RFA):

…for a $30 million, "multi-site, randomized, double-blinded, placebo-controlled trial investigating the efficacy and safety of EDTA (ethylene diamine tetra-acetic acid) chelation therapy in individuals suffering from Coronary Artery Disease.[1]" The ACAM's influence was explicit: "It is expected that the trial will investigate the EDTA Chelation treatment protocol recommended by ACAM." It was also implicit: "Common conventional medical treatments for CAD include percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery, procedures that are invasive and costly.[1]" There was no mention of statins, aspirin, angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, nitrates, antihypertensives, smoking cessation, diet, exercise, or other common "conventional" medical treatments for CAD.

he RFA cited several articles by Edward McDonagh, the chelationist who had previously admitted in a court of law to having falsified his data.[44] The 2001 and 2003 TACT protocols contain at least 5 more references to studies by McDonagh, including one purporting to show that chelation is not nephrotoxic and another purporting to show that it does not cause bone loss.[174,175] The protocols misrepresent a large part of the rest of the chelation literature, as we discuss in Parts III and IV.

The rest, unfortunately, is history. In August 2002, NCCAM announced the $30 million grant award, naming Dr. Lamas as PI. Part of its rationale was in its press release, which cited "the widespread use of chelation therapy in lieu of established therapies [and] the lack of adequate prior research to verify its safety and effectiveness…" and argued that the "public health imperative to undertake a definitive study of chelation therapy is clear." One can't help but note that ACAM had promoted chelation, making it very popular among the "holistic" crowd, and now that very popularity was being used to justify a dubious and expensive clinical trial of chelation. Edzard Ernst had been right in 2000, when he published a review of EDTA chelation therapy for CAD for the American Heart Journal, in which he noted that the literature consisted of numerous enthusiastic but uncontrolled case series countered by a few, exclusively negative controlled trials and concluded: "The most striking finding is the almost total lack of convincing evidence for efficacy. Given the potential of chelation therapy to cause severe adverse effects, this treatment should now be considered obsolete."

Yet NCCAM, Dr. Lamas, and the NIH marched bravely on, and, I bet, Dr. Mandrola was utterly ignorant of this history of TACT1, which I've only summarized briefly from Atwood et al; you (and Dr. Mandrola) should read the whole article.

TACT1 results: Equivocal at best

When the results of TACT1 were presented at the American Heart Association meeting in 2012 and published in 2013, both Dr. Atwood and I discussed the trial again, along with its results, but I'm rather interested on Dr. Mandrola's take first. Let's just say that he was "stunned" and way too impressed. He also perfectly encapsulates the blind spot of EBM, namely the way that it values RCTs above all other evidence and gives little weight to prior probability based on basic science and preclinical studies in assessing treatments:

Let's pause here and pretend we are neutral Martians unencumbered by priors regarding alternative vs traditional medicine.

It is not "encumbered" to consider "priors" with respect to chelation therapy. The priors, as I discussed above, were all negative, making TACT1 unnecessary and highly unethical. We already had more than enough evidence to conclude that chelation therapy does not impact CAD in any meaningful fashion. In fairness, maybe "stunned" isn't so surprising a word to use, but only if you don't know the history of chelation therapy and also how the trial was carried out. Still:

NIH sponsored the trial. Dr. Lamas is a seasoned and established trialist. Co-investigator Daniel Mark also boasts traditional academic credentials. TACT had a proper-placebo control and endpoint. It had long follow-up and enrolled patients who had established heart disease. 

If the treatment were a drug or lucrative procedure, Lamas' presentation of a 41% reduction in major cardiac events in patients with diabetes would have been celebrated and likely sailed through FDA review.

But chelation was not a traditional therapy. Heavy metals were not an established cause of atherosclerosis. So, this was, as Dr. Harlan Krumholz wrote, "inconvenient" evidence.

One might look at it this way. After all, the lack of prior plausibility is not a 100% foolproof reason to reject unexpected findings of a clinical trial. Sometimes, such findings will lead scientists to reassess their understanding of a disease and therapy, leading to major advancements in understanding and treatment. This, however, is not one of those times. For reasons that I will try to explain, it's more akin to trials of homeopathy in that it is incredibly unlikely that even this study points to a scientific mechanism.

Let's start by just looking at the problems with this study, all of which Dr. Atwood and I enumerated in detail. The results as reported did show that 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. As I said at the time, I'm generally suspicious of a composite endpoint of aggregated endpoints like this, as it's always difficult to know whether that composite endpoint represents a true clinical benefit. That suspicion goes double when none of the individual endpoints that make up the composite endpoint hit statistical significance. As I said at the time, the only "signal" of efficacy 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" didn't exist!

As for the findings in diabetics, subgroup analysis (always a questionable analysis that requires replication, even when done in a preplanned fashion, 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 aggregate. As I wrote at the time and keep repeating here, if chelationists had been truly interested in following the results of this trial, they would have immediately stopped using chelation therapy in non-diabetic patients with heart disease, for whom even TACT showed not a hint of a whisper of a benefit. As we know, they did not.

That's not surprising, given that many of the centers where the trial was carried out were "integrative" and alternative medicine practices that offered a panoply of quackery to their patients, as documented by Dr. R. W. Donnell (the blogger who first coined the term "quackademic medicine") in his  Magical Mystery Tour of NCCAM Chelation Study Sites, (Part II, Part III, Part IV, Part V, Part VI, and Part VII). Seriously. As Dr. Donnell pointed out, only 12 of the 110 TACT study sites were academic medical centers. Worse, most 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, anti-aging therapies, assessment of hormone status by saliva testing, and much more. Atwood et al echoed this point by describing how nearly "all chelationist co-investigators are members of an organization or one of its offspring founded 'to promote the use of EDTA chelation therapy for cardiovascular disease'" and listing examples of how they advertised chelation therapy in general and TACT in a manner that suggested subjects would receive chelation for free. Dr. Donnell also made a compelling case that the blinding of the study groups to local investigators was likely to have been compromised. So right off the bat, TACT1 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.

Dr. Mandrola looked at the results this way:

Drs Lamas and Mark did not promote chelation therapy. They did not recommend that people—even those with diabetes—seek chelation.

They were cautious about their surprise findings. The clinical equivalent of their approach was similar to stress testing for finding coronary stenoses. It was as if they had found a positive stress test in a patient with low-risk for heart disease. In the clinic and in trials, you have to consider the priors.

While Drs. Lamas and Mark might have been cautious about their findings, I can't say the same about believers in alternative medicine, who immediately started portraying TACT1 as strong evidence that the "despised" chelation therapy is highly effective and supported by science as a treatment and preventative intervention against atherosclerotic CAD. Some even tried to use it to argue that chelation outperforms statins at preventing the progression of CAD. The promotion of TACT1 to justify their quackery aside, the question, of course, is what to do when the "priors" involved low quality, highly dubious evidence justifying the trial from quacks, political pressure from a powerful antivax Congressman who was also very much into alternative medicine, and a study with all the problems that I described above. Never mind all that though; equivocal results always seem to demand a followup trial, and that's just what happened. Meet TACT2.

TACT2: A completely negative trial, as predicted

Given that TACT2's results were reported as a talk at the at the late-breaking clinical trials session at the American College of Cardiology meeting earlier this month, I can't do my usual deep dive into the paper, as, unlike the case when the results of TACT1 were first reported at a cardiology meeting, I don't have the slide set. All I have are the reporting on the study and the summary on the College website. Basically, TACT2 was a randomized, multi-center, double-blind placebo-controlled clinical trial of EDTA chelation in patients with diabetes and a history of prior myocardial infarction. The treatment involved 40 weekly intravenous infusions of 500 mL EDTA (n = 483) or saline/1.2% dextrose placebo (n = 476). The EDTA infusion included up to 3 grams of EDTA based on each subject's renal function, and each arm was also randomized in a 1:1 fashion to receive an oral high-dose vitamin and mineral supplement or placebo, although the results of this latter part of the trial were not reported. (Not that I'm cynical or anything, but does anyone want to bet that the EDTA/vitamin cocktail will be positive versus placebo in some subgroup or other and that that result will be used to justify continuing to treat heart disease in certain patients with the EDTA/vitamin concoction? Nahhh. Couldn't be. Right?)

The results, after the enrollment of 1,000 subjects showed after a median followup of 48 months:

The primary outcome, composite of time to all-cause death, MI, stroke, coronary revascularization, or hospitalization for unstable angina, for EDTA vs. Placebo, was: hazard ratio (HR) 0.93 (95% confidence interval [CI] 0.76-1.16), p = 0.53

Secondary outcomes for EDTA vs. Placebo:

All-cause death: HR 0.96 (95% CI 0.71-1.30)

Change in median blood lead level from baseline: -5.5 vs. -0.6 µg/L, p < 0.001

Change in median urine cadmium level from baseline: -0.04 vs. 0 µg/g creatinine, p = 0.15

Compliance with all 40 infusions, EDTA vs. Placebo, was: 68% vs. 67%.

In other words, this was as negative as a negative study can be. TACT2 clearly shows that chelation therapy didn't work to decrease progression of or complications from CVD in diabetic patients with a history of previous MI. The authors, however, just had to try to explain why their results were so resoundingly negative:

The original TACT trial demonstrated a modest reduction in death and cardiovascular events associated with EDTA, driven largely by lower rates of coronary revascularization. Given the historically contested reception to chelation therapy for atherosclerotic disease, TACT2 was designed to replicate its predecessor's findings in patients with DM, who derived the greatest benefit compared with placebo in the original study. Surprisingly, no difference in clinical outcomes was observed in this cohort despite similar adherence over a similar follow-up period.

Note, however, his rather bland characterization of chelation therapy as "historically contested." As I hope that you can see from my previous discussion, the reason that chelation therapy has been "historically contested" is, of course, because (1) there was no plausible scientific mechanism for it to cause the regression of atherosclerotic plaques and (2) the more rigorous existing evidence dating back six decades showed that it didn't work on any objective measure used to assess CAD. Moreover, it was actually unsurprising that this study was completely negative. What was surprising was that TACT had produced a positive result. Again, those of us who had been following chelation and TACT, even that result wasn't particularly surprising, as several of us were long predicting that TACT would produce a weakly positive but equivocal result, which is just what it did. None of this stopped the authors from speculating wildly even as they were forced to conclude that chelation is not indicated after MI:

The authors note that this may reflect a smaller potential treatment effect size as blood lead levels in the US and Canada have continued to decrease since the TACT cohort was studied and were even lower in the study cohort compared with contemporary population data. Moreover, a greater proportion of patients in TACT2 were not only taking statins or antiplatelet therapies but also sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, agents with proven cardiovascular benefits that were not available during TACT. The current findings therefore do not support chelation therapy for post-MI patients with DM. Given the outsized benefit originally seen with TACT in this subset further implies that chelation therapy is not indicated regardless of DM status after MI.

Once again, although there is—as Dr. Lamas likes to point out—evidence that elevated lead levels can increase the risk of atherosclerotic disease, there is not—and never has been—good evidence that decreasing lead levels does anything to treat atherosclerosis, but I do like the hand-waving that maybe their negative results are due to the fact that we now have better treatments for type II diabetes that also have cardiovascular benefits. Even if that were true, then maybe we should just abandon chelation entirely in favor of those drugs that actually work.

At this point, you might be thinking: Why are you being so harsh on Dr. Lamas? After all, TACT2 did ultimately conclude that chelation doesn't work for and shouldn't be used in diabetic patients with CAD and history of MI. True, but if you know the history of what happened after the results of TACT1 were reported, you can probably guess what happened after TACT2. Dr. Gervasio Lamas, MD, principal investigator of both TACT1 and TACT2, as well as chair of medicine at Mount Sinai Medical Center in Miami, Florida, did his best spin to explain away the negative results:

Lamas noted that, in addition to the lower lead levels in the TACT2 population, patients in the second study also had more advanced diabetes and more severe associated health impacts than those in the first TACT trial, reducing the trial's ability to meaningfully affect clinical outcomes.

He suggested, however, that the study's findings in terms of overall lead reduction could still be relevant for informing health interventions in the majority of the world where lead exposure is more common.

"Our method of treatment was effective at reducing lead, even in patients starting with low lead levels, and it was safe," Lamas said. 

"In most countries outside of North America and western Europe, lead remains a serious cardiovascular and neurological problem," he said. "This study may be more relevant to those areas of the world, but this is a hypothesis that requires further study."

In other words, Dr. Lamas is still looking for a rationale for a followup study to a completely negative study done as a followup study to an equivocal trial, and Dr. Mandrola is credulous:

Lamas explained at the meeting that lead levels had dropped over time. One study had found that lead levels were 17 mcg/L back in the early 2000s. Now levels are about 11 mcg/dl. 

This is a compelling explanation. Conditions change. We have seen previously effective therapies (aspirin, defibrillators, and post-MI beta-blockers) all lose their efficacy over time because the conditions they treat have become less severe.

Maybe, but not in this case. Again, one notes that no one has actually shown that decreasing lead levels in the blood leads to regression (or even stabilization) of atherosclerotic plaques in CAD. I will give Dr. Mandrola credit for recognizing one thing, though. The likely reason that TACT1 was positive was because of random chance and low statistical power, although he loses points big time for not knowing about all the problems with the trial, including its being carried out mostly at quack clinics, that likely lead to a false-positive signal. He also loses points for making the equivalent argument that TACT2 was negative for the same reason, as if the findings in TACT2 were equally likely to be false-negatives as the findings of TACT1 were to be false-positives.

Then Dr. Mandrola serves up a huge straw man:

The lack of a positive finding in TACT 2 likely closes the chapter on chelation to prevent atherosclerosis. 

It also somewhat dampens our enthusiasm for heavy metals as a modifiable source of atherosclerosis. I added "somewhat" because lead levels were less over time. 

I would not use the non-significance of TACT 2 to conclude that heavy metal exposure is fine. It is clearly not. 

The main lessons here are humility and skepticism. Medical science is hard. We have made great progress. If TACT 1 had studied a new drug or appendage closure device, I am afraid we would have been too accepting.

If only! I only the negative finding in TACT2 would close the chapter on chelation therapy to prevent or treat atherosclerosis! I predict, given Dr. Lamas' equivocating and Dr. Mandrola's credulity towards that equivocating, that it will not, the most likely area of "further study" being overseas in underdeveloped countries, where lead exposure is higher. Moreover, no one—and I mean no one—is using the "non-significance of TACT 2 to conclude that heavy metal exposure is fine." What we are saying is that no one, particularly chelationists, has ever shown that acutely lowering lead levels with chelation therapy treats or prevents atherosclerotic CAD.

As for the last part, I would argue Dr. Mandrola's point a little differently. First, let me preface my different take on Dr. Mandrola's point by referring to a couple of old posts, in which I likened ivermectin as a treatment for COVID-19 to acupuncture and used that analogy to argue that SBM isn't just for "complementary and alternative medicine" or "integrative medicine." Indeed, the widespread adoption of ineffective treatments for COVID-19, even in some academic medical centers, is rooted in the same problem with EBM that leads to RCTs for highly implausible alternative medicine modalities, such as acupuncture and homeopathy: the discounting—or lack of consideration altogether—of "priors," as in prior probability based on consideration of the sum total of previous evidence, but in particular basic science that strongly concludes that a treatment cannot work. With homeopathy, this is an easy point to make, given that homeopathy involves diluting homeopathic remedies to the point where none of the starting material remains, leaving you with water or whatever diluent was used. With acupuncture, there is no evidence that meridians exist or that inserting needles in what are represented as meridians does anything specific for any disease. In the case of ivermectin, the concentration required in cell culture to inhibit SARS-CoV-2, the virus that causes COVID-19 is 50- to 100-fold higher than what can safely be achieved in the human bloodstream.

TACT1 and TACT2 illustrate this problem very well. In fact, I would argue that, unlike the case of ivermectin, which was being tested as a treatment for a novel virus and for which there was little evidence other than the in vitro cell culture work, the evidence base for chelation wasn't just inadequate. It was strongly in favor of the conclusion that chelation doesn't have any clinically meaningful effects preventing or treating CAD, which makes spending $30 million on TACT1 indefensible in the first place, never mind the additional $37 million that never would have been spent on TACT2 if TACT1 hadn't been greenlighted in the first place. Looking at it that way, doing a few RCTs on ivermectin seems more forgivable than spending $30 million on TACT1. Also, one can't help but note another parallel, that of ideologue politicians pushing for ivermectin and for chelation therapy. Quite simply, had there been no Rep. Dan Burton—whom ACAM described in its May 2000 newsletter as a "Wonderful ally"—pushing for TACT1, the trial never would have been funded.

Back to my different take on Dr. Mandrola's observation. If chelation were a new drug or appendage closure device, TACT1 and TACT2 would never have happened. The reason is simple. Pharmaceutical and device companies are loathe to waste tens of millions of dollars to mount a large multicenter RCT of an intervention with a preclinical and clinical evidence base as weak-to-nonexistent as the evidence base that existed in 2000—no, in the 1960s—for EDTA-based chelation as a treatment for atherosclerosis. They abandon the development of such treatments as dead ends and shift their R&D dollars to other, more promising products in their developmental pipelines. (I like to point out that no pharmaceutical company would invest in a large phase 3 RCT of a drug like ivermectin that requires a dose that is at least 50-fold higher than what can safely be achieved in the human blood stream.) Unfortunately, since the formation of NCCAM (now the National Center for Complementary and Integrative Health, or NCCIH), the NIH has been all too willing to sink huge money into treatments with low to nonexistent "priors" based on the the existing preclinical evidence base for them. TACT1 and TACT2 are nothing more than some really spectacular evidence of how quackademic medicine has corrupted medical research.

I do hope that Dr. Mandrola is right about one thing. I keep hoping that TACT2 does finally close the chapter on chelation therapy as a treatment or preventative for CAD. Then I remember Dr. Lamas' excuses and that the second part of the trial, in which groups were randomized to receive placebo or chelation ± the mineral and vitamin cocktail, has yet to be reported even at a cardiology meeting, and despair. Far from being a win for science, TACT1 and TACT2 show just how credulous academic medicine can be and how willing it is to spend huge sums of monehy to put patients at risk unnecessarily to test what is obviously quackery.

New Heart Failure After AF Diagnosis Merits More Attention

After an atrial fibrillation (AF) diagnosis, roughly two out of every five patients will develop heart failure, making it a much more frequent complication than stroke, according to a nationwide study from Denmark.

Moreover, the burden of heart failure in the AF population has remained constant over the past two decades while lifetime risks of stroke have slightly declined during the direct oral anticoagulant (DOAC) era, Nicklas Vinter, MD, PhD (Aalborg University, Denmark), and colleagues report in a study published online in the BMJ this week.

Patients with AF "are often told that the main risk is stroke after the diagnosis, but A-fib is also associated with other complications—for instance, heart failure or myocardial infarction," Vinter told TCTMD, noting that his team conducted the study to better understand the long-term risks of those complications and how they might have changed over time.

He said the study could not capture the severity of heart failure, stroke, or other complications, so future research would be required to delve into the clinical impacts, but added that it's known that patients who have a double diagnosis of heart failure and AF have a very high risk of mortality. "So I think this study underlines . . . That we need to focus even more on the prevention of heart failure, but still we need to improve prevention of stroke as well," Vinter said, pointing out that the lifetime risk of stroke is still around 20%.

I hope the future guidelines will focus more on heart failure. Nicklas Vinter

Commenting for TCTMD, Renate Schnabel, MD (Universitätsklinikum Hamburg-Eppendorf, Germany), said a novel aspect of the study is that lifetime risks of AF and its complications can be compared between two time periods. The slight decline in stroke may be related to the introduction of DOACs, which have made protection against thromboembolism easier and safer compared with use of vitamin K antagonists, or to greater awareness of the need to treat AF to prevent stroke, she proposed.

The fact that the lifetime risk of heart failure was around 40% and didn't change over the two time periods is important to know, Schnabel added. That "really tells us something about the disease burden in the population," she said. "It's important for health economics and that's important for the healthcare system. And we now, with this study, have really very current data that can inform [not only] the healthcare system but also better communication among healthcare professionals and individuals at risk of atrial fibrillation."

Lifetime Risk of AF Rises

For the study, the investigators examined data from Danish national registries spanning 2000 to 2022. The first part of the analysis included more than 3.5 million individuals ages 45 to 95 (median age 48 years; 51.7% women) who did not have AF at baseline. During the entire study period, the lifetime risk of AF was 27.7% overall, with greater risks observed in men and those with higher educational attainment, higher family income, hypertension, heart failure, MI, cardiomyopathy, dyslipidemia, and valvular heart disease.

Splitting the study period into two parts, Vinter et al found that the lifetime risk of AF increased from 24.2% in 2000-2010 to 30.9% in 2011-2022, consistent with prior research. Possible contributors to the rise are improved detection of AF, increased life expectancy, better survival after MI and heart failure, and growing prevalence of key risk factors like hypertension, dyslipidemia, and diabetes, according to the authors.

The second part of the analysis focused on the 362,721 patients (median age 76 years; 46.4% women) who developed AF during the study period and did not have complications at the time of diagnosis; they were followed for incident heart failure, stroke, or MI.

The most frequent complication was heart failure, with a lifetime risk of 41.2%; there was no significant change from the first to the second half of the study period. That lifetime risk was greater than what was observed for any stroke (21%), ischemic stroke (13%), and MI (12%).

In contrast to what was seen with heart failure, however, lifetime risks declined for the other complications between the first and second halves of the study period—by 5.2% for ischemic stroke, 3.9% for MI, and 2.5% for any stroke. These changes were similar in men and women.

Contributing to the slight decline in stroke risk, Vinter et al say, could be the incorporation of evidence regarding better treatments into AF guidelines over the past few decades or the influence of having more lower-risk patients with AF due to enhanced awareness and earlier detection of the arrhythmia.

Important to consider when interpreting the findings, according to senior author Ludovic Trinquart, PhD (Tufts Medical Center, Boston, MA), is that Denmark, in contrast to some other parts of the world, including the United States, has very high rates of both anticoagulation initiation and adherence among patients newly diagnosed with AF. The lifetime risk of stroke "decreased, but only by less than 3 percentage points," he stressed. "So I think it highlights that there are still opportunities to improve stroke prevention."

Expanding the Focus Beyond Stroke

Trinquart said these findings could be used to inform future changes to AF guidelines, which currently focus on stroke prevention and management. "There is an opportunity to improve recommendations for management focusing beyond stroke risk management, and there is also probably a need to evaluate interventions and therapies focusing on heart failure prevention," he told TCTMD.

Vinter agreed, saying, "I hope the future guidelines will focus more on heart failure."

Asked whether heart failure risk after an AF diagnosis is getting the appropriate attention, Schnabel said, "probably not yet," adding that the high risk of stroke is easier for patients to understand and that "everybody fears debilitating stroke." Moreover, she said, DOACs provide a good treatment option for reducing that risk.

On the other hand, "it's more difficult, I think, in communication and understanding for heart failure, although we certainly know that heart failure is the most common cause of death in atrial fibrillation patients," Schnabel said. "This is known also to healthcare professionals, but it's probably the emotionality that is behind stroke that really puts it into the foreground."

It's probably the emotionality that is behind stroke that really puts it into the foreground. Renate Schnabel

Schnabel noted that rhythm-control therapies, like catheter ablation, have been shown to improve outcomes for patients AF and heart failure, including those with advanced disease, and that novel heart failure therapies like sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be beneficial as well. "But this is rather new and has come to the patient over the last 5 to 10 years, and maybe it will take some more time for the effects to develop, so that maybe in the future we see a lower risk of incident heart failure," she said. "But still, with the high comorbidity burden, I think heart failure will be a major outcome that we need to prevent in atrial fibrillation patients."

More broadly, however, this study "is also a call to action to address known risk factors, identify new risk factors for atrial fibrillation, and detect the disease earlier," Schnabel said. "And this means that we should take atrial fibrillation prevention, detection, and treatment very seriously because it poses a significant burden" around the world.

In an accompanying editorial, Jianhua Wu, PhD (Wolfson Institute of Population Health, Queen Mary University of London, England), and Ramesh Nadarajah, MB BChir, PhD (University of Leeds, England), also argue for expanding the scope of AF management.

"Interventions to prevent stroke have dominated atrial fibrillation research and guidelines during the study period in Vinter and colleagues' analysis, but no evidence suggests that these interventions can prevent incident heart failure," they write. "Alignment of both randomized clinical trials and guidelines to better reflect the needs of the real-world population with atrial fibrillation is necessary because further improvements to patient prognosis are likely to require a broader perspective on atrial fibrillation management beyond prevention of stroke."

Among Diabetes Patients, SGLT2 Inhibitors Less Likely To Cause Gout Compared To Sulfonylureas: JAMA

USA: The use of SGLT2 inhibitors versus sulfonylureas was associated with a lower risk of incident gout, heart failure (HF), and major adverse cardiovascular events (MACEs), and lower rates of recurrent flares in a population-based cohort study of 34 064 adults with type 2 diabetes (T2D). The study findings were published online in JAMA Internal Medicine on April 15, 2024.

"The gout and cardiovascular benefits associated with sodium-glucose cotransporter-2 inhibitors (SGLT2i) in these target trial emulations may guide the selection of glucose-lowering therapy in type 2 diabetes patients, at risk for or with gout," the researchers wrote.

Gout, characterized by recurrent attacks of inflammatory arthritis, stands as a formidable challenge for individuals grappling with type 2 diabetes. The intricate interplay between metabolic dysregulation, insulin resistance, and purine metabolism sets the stage for elevated uric acid levels, predisposing diabetic patients to gout flares. Against this backdrop, pharmacotherapeutic interventions assume pivotal significance in mitigating gout risk while navigating the complexities of diabetes management.

SGLT-2 inhibitors, hailed for their pleiotropic benefits beyond glycemic control, have emerged as p