This transcript has been edited for clarity.
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.
The EDTA worked. The level of lead was very different. In fact, when you look at the epidemiologic studies, there are very little data that tell you how much damage to the vasculature a lead level between 0 and 10 µg/dL is going to do.
Our hypothesis — and I want to emphasize that this is a hypothesis — is that you do two things exactly the same, and what's different is your target of therapy, which has been going down. The public health doctors have done a great job. The politicians, even, have done a great job. We now find that we can't detect a benefit. It's conceivable that if we did a 10,000-patient study or something, we could.
Ward: In fairness, this is a quite time-intensive intervention.
Lamas: It is really tedious. It's 40 infusions, and each one lasts 3 hours.
Ward: That's weekly.
Lamas: Once a week. We tried to be realistic and as kind as possible. Nobody does 40 weeks in a row. People want to visit their grandchildren in the summer. We just asked them to try to finish it within a year.
Ward: What was the compliance in TACT2?
Lamas: Overall,40 infusions were received by 68% of the patients, which I actually think was spectacular, and 20 infusions were received by 78%. Pretty much, on the nose, exactly like TACT. It should have worked if the premise was correct.
Environmental Toxins Still a Risk
Ward: Do you think the takeaway from this is that we've done a good job with environmental toxins?
Lamas: I think that we've done a good job with lead. Lead has made it into the legislature and into the law much better than others. Much better than cadmium, for example, and much better than arsenic, etc. EDTA is pretty specific for lead and cadmium. I do think that we need a stronger cadmium chelator.
We still have events like Flint, Michigan, which was kind of a big event; Newark, New Jersey; Baltimore; and parts of the South. What happens is that lead, when you look at the worldwide map of lead levels, is seen where there is poverty.
Ward: You mentioned that you actually had a site in Flint, Michigan.
Lamas: We had one site in Flint, Michigan. They enrolled two patients.
Ward: Isn't that part of the problem with this solution — the very people who would need it are probably the very people who don't have 3 hours a week to spare?
Lamas: The way that I look at it is that the people we enrolled were individuals who probably had a cardiologist who was participating in the study, which means that they probably had a job and health insurance, or they were retired and they had the time. We ended up not selecting patients on the basis of their lead level because of not having had the lead levels in the first study. If I had to do it again, of course, I would figure out how to find the people with the highest lead level, and it might be outside the US.
Ward: For some clinicians, with things like environmental toxins, it's a little overwhelming. They feel that's maybe something society at large has to address rather than me, a physician in a clinic.
Lamas: You know what? Hypertension has to be addressed on a societal basis. Obesity has to be addressed in a societal basis. Yet, there are people sitting in front of me who are obese and hypertensive, and I address it on an individual basis.
This division between "this is them" and "this is us" doesn't really cut it. We now have this specter of microplastics. That's a tough one. We're not even quite sure how to measure it, but we do know that they exist.
Ward: You're referring to the recent New England Journal of Medicine paper.
Lamas: Yes. The recent paper showing that, if you have microplastics in your carotid atheroma, you're more likely to have cardiovascular events. We need to figure out how to measure that. We also need to figure out how the body gets rid of it — or does it? For example, I haven't looked into this in detail, but one of the things that I need to do is look at urine. Does it come out in the urine? I don't know.
Ward: Is your next study going to be on plastics?
Lamas: No, my next study is to finish the revisions of my paper so I can get TACT2 published.
Ward: Is there anything else you'd like to say? You wrote the American Health Association statement on contaminant metals as cardiovascular risk factors.
Lamas: Right. It's all correct.
Ward: It's still correct?
Lamas: Yes, it's still correct.
Ward: Thank you very much for your time.
Lamas: Thank you.
Ward: This is Tricia Ward, signing off for Medscape.
COMMENTARY
Chelation Therapy and CV Risk: Why TACT2 Showed No Benefit
Tricia Ward; Gervasio A. Lamas, MD
DISCLOSURES
| April 16, 2024This transcript has been edited for clarity.
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.
The EDTA worked. The level of lead was very different. In fact, when you look at the epidemiologic studies, there are very little data that tell you how much damage to the vasculature a lead level between 0 and 10 µg/dL is going to do.
Our hypothesis — and I want to emphasize that this is a hypothesis — is that you do two things exactly the same, and what's different is your target of therapy, which has been going down. The public health doctors have done a great job. The politicians, even, have done a great job. We now find that we can't detect a benefit. It's conceivable that if we did a 10,000-patient study or something, we could.
Ward: In fairness, this is a quite time-intensive intervention.
Lamas: It is really tedious. It's 40 infusions, and each one lasts 3 hours.
Ward: That's weekly.
Lamas: Once a week. We tried to be realistic and as kind as possible. Nobody does 40 weeks in a row. People want to visit their grandchildren in the summer. We just asked them to try to finish it within a year.
Ward: What was the compliance in TACT2?
Lamas: Overall,40 infusions were received by 68% of the patients, which I actually think was spectacular, and 20 infusions were received by 78%. Pretty much, on the nose, exactly like TACT. It should have worked if the premise was correct.
Environmental Toxins Still a Risk
Ward: Do you think the takeaway from this is that we've done a good job with environmental toxins?
Lamas: I think that we've done a good job with lead. Lead has made it into the legislature and into the law much better than others. Much better than cadmium, for example, and much better than arsenic, etc. EDTA is pretty specific for lead and cadmium. I do think that we need a stronger cadmium chelator.
We still have events like Flint, Michigan, which was kind of a big event; Newark, New Jersey; Baltimore; and parts of the South. What happens is that lead, when you look at the worldwide map of lead levels, is seen where there is poverty.
Ward: You mentioned that you actually had a site in Flint, Michigan.
Lamas: We had one site in Flint, Michigan. They enrolled two patients.
Ward: Isn't that part of the problem with this solution — the very people who would need it are probably the very people who don't have 3 hours a week to spare?
Lamas: The way that I look at it is that the people we enrolled were individuals who probably had a cardiologist who was participating in the study, which means that they probably had a job and health insurance, or they were retired and they had the time. We ended up not selecting patients on the basis of their lead level because of not having had the lead levels in the first study. If I had to do it again, of course, I would figure out how to find the people with the highest lead level, and it might be outside the US.
Ward: For some clinicians, with things like environmental toxins, it's a little overwhelming. They feel that's maybe something society at large has to address rather than me, a physician in a clinic.
Lamas: You know what? Hypertension has to be addressed on a societal basis. Obesity has to be addressed in a societal basis. Yet, there are people sitting in front of me who are obese and hypertensive, and I address it on an individual basis.
This division between "this is them" and "this is us" doesn't really cut it. We now have this specter of microplastics. That's a tough one. We're not even quite sure how to measure it, but we do know that they exist.
Ward: You're referring to the recent New England Journal of Medicine paper.
Lamas: Yes. The recent paper showing that, if you have microplastics in your carotid atheroma, you're more likely to have cardiovascular events. We need to figure out how to measure that. We also need to figure out how the body gets rid of it — or does it? For example, I haven't looked into this in detail, but one of the things that I need to do is look at urine. Does it come out in the urine? I don't know.
Ward: Is your next study going to be on plastics?
Lamas: No, my next study is to finish the revisions of my paper so I can get TACT2 published.
Ward: Is there anything else you'd like to say? You wrote the American Health Association statement on contaminant metals as cardiovascular risk factors.
Lamas: Right. It's all correct.
Ward: It's still correct?
Lamas: Yes, it's still correct.
Ward: Thank you very much for your time.
Lamas: Thank you.
Ward: This is Tricia Ward, signing off for Medscape.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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