Chelation therapy fails to improve cardiovascular outcomes after heart attack: TACT2
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Key takeaways:
- Chelation therapy involves IV infusions of an agent that binds to metals such as lead and cadmium and is excreted in urine.
- Chelation therapy did not yield clinical benefit in post-MI patients with diabetes.
ATLANTA — In the TACT2 trial, chelation therapy reduced levels of lead in the blood but did not improve cardiovascular outcomes for adults with diabetes and a prior heart attack.
“TACT2 does not support the use of edetate disodium chelation for risk reduction in stable post-MI patients with diabetes,” Gervasio A. Lamas, MD, chair of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami, said during the late-breaking clinical trial presentation at the American College of Cardiology Scientific Session.
Edetate disodium-based chelation is a therapy that draws lead and other toxic metals linked to risk for CVD and stroke out of the body.
The TACT2 results come a decade after the original TACT trial was published. (See Healio’s coverage here.) The TACT trial, which ran from 2003 to 2012 and involved 1,702 patients with prior MI, suggested modest benefits from edetate disodium-based infusions for reducing CV events over a median follow-up of 55 months, especially in people with diabetes. TACT2 was designed to replicate the TACT findings in post-MI patients with diabetes and measure the effect of repeated edetate disodium infusions on blood lead and urine cadmium, Lamas said.
No difference in outcomes
TACT2 was conducted from 2015 to 2020. The trial involved 1,000 patients with type 2 diabetes (> 90%) and a prior MI at 88 sites in the U.S. and Canada. Patients were randomly assigned to 40 weekly infusions of edetate disodium or placebo.
The mean age of participants was 67 years, 27% were women and 61.5% were non-Hispanic white. Median time from MI to randomization was 5 years. Mean HbA1c was 7.5%. Nearly half of the patients were on insulin and one-quarter on a GLP-1 or SGLT2 inhibitor. Use of aspirin, warfarin, P2Y12 inhibitors, beta-blockers and statins was high.
“Edetate disodium did not result in a significant clinical benefit on primary or secondary endpoints or on all-cause mortality,” Lamas said.
During a median follow-up of 48 months, there was no significant difference between chelation therapy and placebo for the primary endpoint of time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization or hospitalization for unstable angina, which occurred in about 35% of patients in both groups (adjusted HR = 0.93; 95% CI, 0.76-1.16; P = .53). Lamas also reported no significant difference in secondary endpoints including recurrent events of the primary composite endpoint, all-cause mortality, and a composite of CV mortality, MI or stroke.
Subgroup analyses did not identify any subgroup that would be likely to have greater effects from chelation therapy compared with placebo, Lamas said.
No safety issues were identified.
Reduction in blood levels
Lamas said lead and cadmium are “ubiquitous environmental pollutants” and are also recognized risk factors for atherosclerosis.
“Pre-infusion blood lead levels, a key to determine whether or not what we were infusing reduces blood levels, in the placebo group were not particularly different over time, [but] in the [chelation therapy] group there was a significant reduction — over 60% — which was highly significant (P < .001),” Lamas said.
Pre-infusion cadmium levels did not significantly change over time.
Why the difference between TACT and TACT2?
Lamas discussed possible reasons for the difference between the TACT and TACT2 trials.
“[National Health and Nutrition Examination Survey data] shed a little bit of light,” he said. “In 2003 to 2010, when TACT was in operation, blood lead levels in the U.S. were 17 µg/L. Due to public health interventions between 2015 and 2020, when TACT2 was in operation, blood lead levels were 10 µg/L, a 41% drop. And TACT2 blood lead levels were even lower at baseline: 9 µg/L.
“Our hypothesis is that blood lead levels have markedly dropped since 2003, possibly reducing the potential therapeutic impact of further lowering blood lead levels,” Lamas said.
Lamas also noted that different populations within North America may have inordinate lead contamination. For example, one of the 88 sites that enrolled patients for TACT2 was in Flint, Michigan, he said.
“If we had to do it over again, I think that lead level would be an entry criterion,” Lamas said. “In the developed world, lead levels are probably in the range of 10 µg/L or below as an average at this point. ... On the other hand, lead levels in poorer countries are in the range of 60 µg/L. In wealthy or higher-income countries, it is at 14 µg/L.
“Perhaps [the message is not] ‘chelation doesn’t work,’ but rather if you are using a treatment that is specific for a toxin, make sure the toxin is present in the group you are using. It was present way back when; it is less present now because public health in the U.S. and Canada has been focused on lead levels.”
During a discussion of the TACT2 results, Richard Chazal, MD, MACC, cardiologist with Lee Health in Fort Myers, Florida, said this should “help clarify what is a perplexing problem with patients coming to us and asking about [chelation therapy].”
Perspective
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Suzanne J. Baron, MD, MSc, FSCAI
Certainly, we have seen an explosion of new treatments for patients with CAD over the last decade. Beyond statins, there are new lipid-lowering medications, such as the PCKS9 inhibitors and the antidiabetic drugs, particularly the SGLT2 inhibitors and GLP-1 receptor agonists, which have been shown to decrease CV mortality.
While it is possible that the potential benefit of chelation therapy may have been blunted by these other agents, all of which represent significant advancements in the field of CV care, TACT-2 was a definitive, well-conducted trial which showed that chelation therapy in patients with diabetes who have had an MI did not result in better CV outcomes in the current era. The questions raised by the original TACT trial have been answered, and it makes sense to move onto the next research question.
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Lamas GA, et al. Joint American College of Cardiology/New England Journal of Medicine Late-breaking clinical trials III. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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