Chelation Therapy and CV Risk: Why TACT2 Showed No Benefit

Tricia Ward interviews Gervasio Lamas TACT2, a trial of chelation therapy to lower CV risk presented at the 2024 ACC Scientific Sessions, and why its findings differed from those of TACT.
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-- TRANSCRIPT --
Tricia Ward: Hi. I'm Tricia Ward from theheart.org | Medscape Cardiology. I'm at the 2024 American College of Cardiology Scientific Sessions in Atlanta, where I'm joined today by Dr Gervasio (Tony) Lamas. He is chairman of medicine and chief of the Columbia University Division of Cardiology at Mount Sinai Medical Center. Welcome, Dr Lamas.
Gervasio A. Lamas, MD: Thank you, Tricia.
Ward: You just presented TACT2, a trial of chelation therapy in patients with diabetes and prior myocardial infarction. Can you tell us the topline findings?
TACT2: Neutral for Chelation Therapy
Lamas: The topline findings are that the study was negative and did not show any benefit for chelation in our US and Canadian patients who had established coronary disease with a heart attack and also had diabetes compounding that.
What is chelation? A chelating agent is a chemical compound that has a particular shape with a pocket. It's like a baseball mitt with a magnet in it. The one that we're talking about is ethylenediaminetetraacetic acid (EDTA), or edetate disodium, which is the US Food and Drug Administration (FDA) designation.
The original study was TACT, which ran from 2003 until 2012. This study has exactly the same design. We identified patients who had a prior heart attack, had reasonably good kidneys, were at least 50 years of age, and were not smokers. The reason they couldn't be smokers is that cigarette smoke has a large amount of lead and cadmium. We randomly assigned them to receive 40 infusions of the chelation or 40 infusions of placebo.
Everyone thought that this study was going to be negative. In fact, I was shocked when TACT turned out positive. Then I had to do backpedaling and scrambling to figure out by what mechanism this could have been. It turns out that it was obvious. EDTA chelates lead and cadmium. They're both vascular poisons because they take the place of essential metals in our body.
We had this surprise result with an 18% relative risk reduction in all-comers with a prior heart attack that was statistically significant, and a spectacular 41% relative risk reduction in the patients who had diabetes. The FDA said, "Well, this is very interesting. Why don't you do it again?"
A couple of years passed, and TACT2 started. The first patient was randomized in 2016. We randomized 1000 patients. We had the same team, same protocol, same data coordinating center (Duke Clinical Research Institute), same clinical events committee at Brigham and Women's in Boston and then at Stanford, and the same batch of EDTA made by the same manufacturer.
Lead Exposure Declined Over Time
Ward: One of the reasons you think the result was different was because of the lead level?
Lamas: We realized that, in the decade plus that occurred between the start of TACT and the start of TACT2, lead levels in the United States and Canada had been dropping rapidly. We didn't collect [those data] in TACT because we weren't supposed to spend any extra money.
The National Health and Nutrition Examination Survey (NHANES) is a national survey that's representative of the US. For patients aged 50 years with diabetes and vascular disease, [we can estimate from NHANES that] the lead levels were 17 µg/dL in TACT. In TACT2, their lead levels were 10 µg/dL. The people we randomized - because we were smart enough now for TACT2 to order trace elements labs - had levels of 9 µg/dL. You see that what we are now doing is the equivalent of trying to reduce cholesterol in people who don't have high cholesterol.
Ward: The chelation did actually work in terms of reducing the lead levels.
Lamas: The next step is, did your chelation work? If you look at blood lead level as a representative of your total body lead burden, that went from 9 µg/dL to 3 µg/dL, so over 60% reduction. The drug works. If you look at cadmium, the total body burden of cadmium is thought to be best reflected by cadmium in the urine. That didn't change so much. Still, when we gave the infusions, cadmium excretion increased by about 600%, which means that we have a large amount of cadmium in our bodies.
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