Trial to Assess Chelation Therapy (TACT), EDTA chelation, Diabetes, Heart attack, Limb ischemia, Cardiovascular illness

A Personal Account of The Trials to Assess Chelation Therapy – the End of the Beginning?

By Gervasio A. Lamas MD FACC FAHA FESC

Principal Investigator TACT program

Chairman of Medicine, Mount Sinai Medical Center

Chief of Cardiology, Columbia University Division of Cardiology at Mount Sinai

Professor of Medicine, Columbia University School of Medicine

Introduction

To the reader: This is meant to be a scientific article but written in a narrative style for the Townsend Letter to improve its readability and decrease boredom. I do digress and share some personal details so the reader may gain a better understanding of the origin of this unique study and the future lines of study it engendered. The materials I discuss have all been peer reviewed and published and presented—most as full-length papers, some as abstracts—and the distinction is clear in the references. To the best of my ability, I always lean towards a conservative interpretation of the data.

Digression

Me. Typical “immigrant makes good” story: I left Cuba at age 8 for Miami. I lucked out by being accepted to Harvard, then NYU medical school. I again lucked out by being accepted to the best, bar none, internal medicine and then cardiovascular program in the US – the Brigham and Women’s Hospital of Harvard Medical School. I stayed as Harvard faculty for an additional 9 years. Those 15 years at the Brigham imprinted an uncompromising pursuit of excellence, the value of science, and a certainty that if you have clean data, you can save lives. I started working on clinical trials in the 1980s with incredible mentors and never looked back.

While this seems a digression, I want to make sure that the reader understands that I come from a completely conventional, albeit excellent medical education and background.

The Beginning

This takes us to 1999. I was chief of cardiology at Mount Sinai Medical Center in Miami Beach, Florida, having built an academic division within a community hospital. My first trial, on heart pacemakers, funded by the National Heart, Lung, and Blood Institute (NHLBI) was well under way, and all was right in my happy bubble of patient care, teaching, and research.

Then in August of 1999 I saw an unusual consultation for a new patient. He was mildly shabby in the style of Peter Falk’s Lt. Columbo character, and he wanted EDTA (ethylenediamine tetra acetic acid) chelation. I told him that chelation was nonsense, quackery, expensive, and probably dangerous. So he left.

Later I realized I had been rude. And while I could not undo rudeness, I figured I would feel less rude if I could prove to myself that what I had said was right – so I hit the books and tortured the hospital librarian. In reality my having to go to the library was proof that I had spoken out of bias and ignorance and should have kept my mouth closed.

Before Planning TACT

I learned that EDTA was an artificial amino acid first synthesized in Germany in 1937, and that medical use started about a decade later. By the 1950s the medical community used infusions to treat high blood calcium levels and even toxicity from the only cardiac drug of the era, digoxin. EDTA, a chelating agent, is like a baseball mitt with a magnet inside, a molecule with a pocket. The baseball that sticks in the center is a small ion with a positive charge, like calcium, lead, cadmium, and many other charged particles. Once it sticks, the kidneys harmlessly excrete the EDTA and the small particle. Because EDTA has a magnetic charge, it always travels with sodium, calcium, or magnesium.

The 1950s were the Stone Age of cardiology; we really had no drugs, no catheterization, no stents, no bypasses, no statins, no aspirin use to prevent heart attacks. It was the ham and eggs with a cigarette for breakfast era. When patients died of a heart attack and went to autopsy, the coronary arteries, whose job it is to feed the pumping heart muscle, were plugged up and their walls were full of calcium. So on the one hand were calcified arteries and on the other hand a drug that bound calcium. Some smart docs decided that perhaps this might be a match made in heaven and tried disodium EDTA infusions—this is the EDTA that takes out calcium. Much to their surprise, of 20 patients with severe coronary disease, 19 showed improvement. This first paper of EDTA for coronary disease¹ was published in 1956! But EDTA did not get the expected boost, or patients the potential benefit. It is not clear to me why chelation did not spread like wildfire, but it did not. In the 1960s some tiny clinical trials suggested that benefit might be less than expected, and chelation dropped off the scene. By the 1970s it had jumped to the realm of alternative medicine and practiced by what traditional practitioners called quacks. In the 1980s and early 1990s all medical associations, for the most part, either ignored chelation or declared it ineffective nonsense. State medical boards censured chelation practitioners. But the practice of chelation persisted.

Alternative medicine physicians published that there was vascular benefit.² These publications were case series in non-mainstream journals, and cardiologists did not read them. Mainstream cardiology journals published additional small, better-designed studies in the 1990s and early 2000s. These studies showed no benefit of chelation for relief of symptoms of atherosclerosis. On the other hand, the studies were not large enough to exclude a small to moderate benefit of chelation on clinical events like heart attacks. And this is where matters stood when my patient walked in to ask for chelation in August of 1999.

I decided that modern clinical trials methodology could address the lingering question of chelation for coronary artery disease, and called a Deputy Director I knew at the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). Much to my surprise, he said they were interested in seeing a proposal from a clinical trialist. The background here is that, unbeknownst to me, for years leading chelation practitioners had been pleading for a chelation trial. They had the ear and support of powerful congressmen and senators, who had put pressure on NHLBI to study chelation; but there had been no proposals forthcoming from established clinical scientists, till I walked in – better lucky than smart.

TACT

There are four essential elements to an NIH clinical trial: an idea, a team, funding, and obsession. With chelation, there are no pharma companies who stand to make billions. You are chronically underfunded. You push through because of obsession. And I was hooked.

I gathered the “A” team: I provided obsession; my small team at Sinai would coordinate all the moving parts; the Duke Clinical Research Institute would lead data collection and statistics; clinical events would be evaluated at Harvard. The work would be carried out at hospitals and clinics in the US and Canada, including Hopkins and Mayo, as well as many alternative medicine practices. All the parts would be connected by a new computerized data collection and study management system. Three years later, in August of 2002, Mount Sinai Medical Center of Florida, my hospital, received a federal grant of $30 million to carry out the Trial to Assess Chelation Therapy (TACT). Once the study design was finalized, and FDA and NIH gave their okay, we were off and running. The first patient was enrolled in September 2003.

The TACT design is well known.³ We randomly assigned patients with a prior heart attack who were at least 50 years old and had at least fair kidney function to 40 edetate disodium chelation or placebo infusions – 30 weekly infusions followed by 10 maintenance infusions.

The active infusions contained up to 3 g of edetate disodium, adjusted for kidney function, 2 g of magnesium chloride, 100 mg of procaine HCL, 2500 U of heparin, 7 g of ascorbate, 2 mEq KCl, 840 mg sodium bicarbonate, 250 mg pantothenic acid, 100 mg of thiamine, 100 mg of pyridoxine, and sterile water to complete 500 mL.

Chelation practitioners in the community always give high doses of oral multivitamins and multiminerals in conjunction with chelation, so we developed a high dose vitamin and mineral regimen for patients to take throughout the entire study that was also placebo controlled. Because it was such a rich oral supplement, patients had to take 3 large pills twice daily. As the reader can see, this becomes two studies in one: Active IV chelation vs. Placebo IV chelation, and Active oral high-dose vitamins vs. Placebo oral “vitamins”. The most interesting comparison here is that of the patients taking “active-active” vs. “placebo-placebo,” shaded in Table 1. But we will get to that.

Table 1. Factorial randomization in TACT: two studies in one

We had decided to study patients who’d had a prior heart attack, were at least 50 years of age, and had at worse, fair renal function. The primary endpoint of the study—what we were trying to prevent—was a laundry list of all the bad things that can occur to cardiac patients: death, stroke, recurrent heart attack, stents or bypass, and hospitalizations for cardiac pains. We also decided to look at patients with diabetes as a separate group.

The study took 10 years to complete, instead of the expected five. We enrolled slowly in a tough study with a lot of patient burden, every minute compounded by controversy. Misguided scientists and hostile reporters tried to stop the trial. But, here is where a clean “A” Team study reinforced with obsession counts—we were unstoppable and science triumphed. Eventually we counted 134 enrolling sites in the US and Canada enrolling 1708 patients. We administered 55,222 infusions and spent innumerable hours managing the sites all the while dodging arrows of controversy.

Like all the best NIH clinical trials, TACT employed a double-blind design. So after 10 years, only a select group of statisticians, NIH scientists, and a supervisory board had seen unblinded results. I was not in that group. So picture the unblinding ceremony. We sat at a long table at Duke—blinded clinicians on one side and about 10 statisticians on the other side. We spent about 30 minutes dying through some conversation. Finally, the Duke team distributes the unblinded data books. We speed to the right pages. I address Kerry Lee, PhD, professor of biostatistics, “Kerry, are you telling me this is a positive study?” “Why yes, Tony. It is.”

OOPS. The study we conceived 13 years before, which was supposed to show chelation was nonsense, instead showed that it reduced cardiovascular events. I put my head on the table. I knew that one way or another, the “A” Team would have to do it again—unexpected results have to be reproduced.

We wrote up our results and submitted to the leading medical journal. We received a Bronx raspberry by return mail. We then opened negotiations with the next best journal, which was led by more open-minded scientists. It took about half a year of negotiating and rebutting critiques, before we received the coveted acceptance letter to the Journal of the American Medical Association.⁴ In the meantime, I presented at the American Heart Association. Big meeting—lots of media—I was treated as I imagine a medieval leper might have been…quite disappointing. But who cares, after all. We had stumbled across a new way to treat patients with heart attacks; we were flying high, leaving the critics in the dust.

So, what did we learn?

• In patients with a prior heart attack, a course of edetate disodium-based chelation reduces recurrent cardiac events by 18% (Figure 1).⁴

• In patients who are on double active therapy (chelation +oral vitamins), compared with double placebo, events are reduced by 26%.

• In patients that have diabetes as well as a prior heart attack we reduced the risk of a subsequent cardiac event by 41%; the risk of another heart attack by about 50%, and the risk of death by 43% (Figure 2).⁵

Along the way we also learned that after a TACT infusion, the amount of lead in the urine increases by nearly 4000%, and cadmium nearly 700%.⁶ We are all polluted. We also learned that low-level lead exposure may be responsible for hundreds of thousands of deaths annually.⁷ So our results made sense.

At this point I really found out who were the real scientists. Our NIH supervisors and colleagues had walked the same path for a decade and knew the data were clean; they were excited about a new way to treat atherosclerosis. They came with us to FDA. Predictably, FDA said, “Nice study, do it again.” And so, the “A” Team committed to another decade of chelation research.

Enter TACT2

On September 27, 2016, Mount Sinai received an NIH grant for $36 million for TACT2. Same design as TACT1, but now restricted to patients with a heart attack who also had diabetes. But now we have broad NIH support, and we are also keeping a biorepository to assess changes in toxic metals and more. Long and short of this, we expect to report on 1100 patients in 2023. In the meantime, we are blinded – boring and frustrating, but necessary.

Enter TACT3a

Still, we are not sitting on our hands. Mount Sinai and the James Carter Estate funded a pilot study of patients with diabetes and critical limb ischemia, including gangrene. I have seen gangrene regress and have saved legs.⁸ But nothing is real without a placebo control, so the Florida Heart Research Foundation and a generous private donor teamed up to allow us to start TACT3a. This is a small, placebo-controlled, randomized trial of 50 patients with critical limb ischemia.

What Do We Need?

At this point we are on track with the TACT program, but we need patients. We need TACT2 patients (diabetes, prior heart attack), and TACT3a patients (diabetes and critical limb ischemia).

Please visit our website www.tact2.org for all the papers and results referenced here, as well as lectures and more. You can reach me through the website.

References

1. Clarke CN, Clarke NE, Mosher RE. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Med Sci. 1956;232(6):654-66.

2. Olszewer E, Carter JP. EDTA chelation therapy in chronic degenerative disease. Med Hypotheses. 1988;27(1):41-9.

3. Lamas GA, et al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 2012;163(1):7–12.

4. Lamas GA, et al, TACT Investigators. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241–1250.

5. Escolar E, et al. The effect of an EDTA based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014;7:15–24.

6. Arenas IA, et al. Enhanced vasculotoxic metal excretion in post-myocardial infarction patients following a single edetate disodium-based infusion. Environ Res. 2017 Oct;158:443-449.

7. Lanphear BP, et al. Low-level lead exposure and mortality in US adults: a population-based cohort study. Lancet Public Health. 2018 Apr;3(4):e177-e184.

8. Ujueta F, et al. Edetate Disodium-Based Treatment in a Patient With Diabetes and Critical Limb Ischemia After Unsuccessful Peripheral Arterial Revascularizations: A Case Report. Clin Diabetes. 2019 Jul;37(3):294-297.

Figures

Event curves showing chelation in blue and placebo in red in patients with a prior heart attack. There are fewer cardiac events – death, heart attack, stroke, stents, cardiac bypass, or hospitalization for chest pains – in patients receiving chelation.

Figure 2

Event curves showing chelation in blue and placebo in red for patients with a prior heart attack and diabetes. There are fewer cardiac events – death, heart attack, stroke, stents, cardiac bypass, or hospitalization for chest pains – in patients receiving chelation.