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ATLANTA -- Chelation to remove lead and other heavy metals didn't improve outcomes for type 2 diabetes patients after myocardial infarction (MI), the TACT2 trial showed.

Cumulative incidence of time to first event (MI, stroke, hospitalization for unstable angina, coronary revascularization, or death from any cause) was no different than with placebo infusions (HR 0.93, 95% CI 0.76-1.16).

And despite the fact that edetate disodium (EDTA) chelation cut serum lead levels by more than 60%, all-cause mortality likewise showed no impact of chelation (HR 0.96, 95% CI 0.71-1.30), Gervasio A. Lamas, MD, of Mount Sinai Medical Center in New York City, reported at the American College of Cardiology (ACC) annual meeting.

Those findings contrasted with results of the initial , which had shown a significant 26% reduction in overall cardiac events by EDTA chelation plus oral vitamins in the two-by-two factorial designed trial. In patients with diabetes, chelation cut those events by 41% and all-cause mortality by 43% over 5 years.

It had been what Lamas previously called a "black swan event," showing an improbable benefit to the dismay of many clinicians.

TACT2 was the confirmatory study requested by the FDA, "testing the most effective drug combination (chelation + oral vitamins) in the population that demonstrated the greatest benefit (post-MI diabetic patients)," he wrote for MedPage Today.

Now it's time to let the concept go for routine use in U.S. practice, he suggested. Still, "the take home message [should not] be 'Chelation doesn't work,' but rather have the take home message be, 'If you are using a treatment that is specific for a toxin, make sure the toxin is present in the group.'"

It has been "sometimes a perplexing problem with patients coming to us and asking us about this," when the 2023 guidelines on chronic coronary disease "express some ambiguity," noted ACC session study discussant Richard A. Chazal, MD, of the Lee Memorial Health System in Fort Myers, Florida.

So why were the results between the two trials so different?

"[National Health and Nutrition Examination Survey data] sheds a little light," said Lamas. That data showed that in the interim between the two trials, serum lead levels dropped by at least 35%, which Lamas chalked up to public health attention focused on the issue after the crisis in Flint, Michigan.

"If I had to do it over again, lead level would be an entry criterion," he said at the session. There are still places in the world where it could be a valuable approach, he suggested. U.S. lead levels average 11 mcg/L, compared with 66 mcg/L in poor countries.

When asked at the session about the next direction for chelation research, Lamas noted the many years it had taken to get to this point. "I'm happy to start but need somebody with a little less white hair to finish."

The TACT2 trial included 1,000 patients age 50 and older who were more than 6 weeks post-MI, had diabetes, a creatinine level no higher than 2.0 mg/dL, and didn't smoke.

They were randomized to 40 infusions of 500 mL of either EDTA with vitamins (up to 3 g based on renal function plus 7 g ascorbic acid and 2 g magnesium chloride) or normal saline and 1.2% dextrose plus oral low-dose vitamin and mineral supplements. The trial also included factorial randomization to vitamin supplementation, but that comparison was not included in the presentation.

Patients had at least 2.5 years of follow-up, with a median of 4 years. Of them, 27% were women and 61.5% were non-Hispanic white. All patients had lead detectable in their blood but at a relatively low median of 9.22 mcg/L.

EDTA is also expected to chelate cadmium, which was detectable in 97% of participants but the median 0.30 mcg/g creatinine in urine didn't drop much in either group (P=0.15).

At the same time, no safety issues were seen, Lamas noted.

Adherence was around 68%, which "given that it was 40 infusions, it was quite good," he said.

"Maybe the full treatment regimen would have been needed to see an effect," suggested ACC press conference study discussant Suzanne Baron, MD, of Massachusetts General Hospital in Boston.

At the same time, treatments have come a long way, she noted, so additional therapeutics might have overcome any benefit chelation was able to offer.

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