ATLANTA, GA—More than a decade after the TACT trial reported an astonishing reduction in cardiovascular events post-MI with heavy metal chelation in a subset of diabetic patients, the TACT2 trial, designed to test edetate disodium (EDTA) solely in a diabetic population, has come up empty-handed.

In 1,000 post-MI patients, EDTA did indeed reduce blood levels of lead by more than 60% but had no significant effects on the occurrence of a composite primary endpoint of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina, or a range of secondary endpoints.

Gervasio Lamas, MD (Mount Sinai Medical Center, Miami, FL), principal investigator for both trials, weathered suspicion and derision in the lead up to the first National Institutes of Health-funded TACT trial but was vindicated when the results, published in 2013, showed an 18% reduction in CV events, overall, and 41% reduction in patients with concomitant diabetes.

Today, however, presenting TACT2 to the late-breaking audience at the American College of Cardiology 2024 Scientific Session, Lamas was sanguine in defeat.

“I’m disappointed, obviously,” he told TCTMD. “My two statements would be: science is a cruel master, and chelation never ceases to surprise.”

The TACT2 Era

TACT2, like its predecessor, randomized patients to 40 weeks of EDTA or placebo infusion and oral, low-dose vitamin and mineral supplements. All patients were over the age of 50, diabetic, nonsmokers, and had had an MI more than 6 weeks prior.

Over a median 48 months of follow-up, rates of the primary composite outcome were nearly identical in the EDTA and placebo infusion groups, as was time to death, with no subgroup faring better than any other.

In an important finding, said Lamas, blood levels of lead dropped from approximately 9 µg/L at the start of the trial to less than 4 µg/L by the studies end, (P < 0.001). That matters, said Lamas, because while TACT2 mirrored TACT in myriad ways—same investigators, same pharmacies, same EDTA—the key difference was the era in which they were conducted. TACT enrolled patients between 2003 and 2012, at a time when environmental lead exposure was far higher, as reflected by NHANES data from 2003-2010 showing that mean lead levels for individuals age 50 or older were 17 µg/L.

By contrast, TACT2 enrolled patients from the US, Canada, and Western Europe between 2015 and 2020 at a time when NHANES data captured population lead levels at a mean of 11 µg/L—35% lower than in the TACT era. “US blood levels have markedly dropped since 2003, possibly reducing the potential therapeutic impact of further lowering blood lead level,” Lamas said.

My two statements would be: science is a cruel monster, and chelation never ceases to surprise. Gervasio Lamas

To TCTMD, Lamas credited the banning of leaded gasoline as a key factor in reducing environmental pollutants. His negative trial, in his mind, stems from a positive population outcome. “I’m annoyed, but my annoyance is mitigated by the fact that I think there’s an explanation and that it’s a positive explanation,” Lamas said.

That said, he continued, “there are many parts of the world where chelation might still be applicable as a disease-modifying strategy.”

During today’s late-breaking session, Lamas pointed out that there are parts of the US where lead levels are higher, so selection bias may have played a role in these neutral results. The trial actually included a site in Flint, MI, which made national headlines in 2014 for the high levels of lead contamination in the city’s drinking water. Unfortunately, only two patients were enrolled at this location, he said.

He also said he will continue to routinely measure blood heavy metal levels in his patients—in part because many are sushi eaters who can have high levels of blood mercury. In his own practice, said Lamas, he has seen lead levels come down with time.

Other Explanations

Suzanne Baron, MD (Massachusetts General Hospital, Boston, MA), who commented on the study during a morning press conference, congratulated Lamas for the “labor of love” needed to get to the bottom of this long-running hypothesis.

“A couple of other things that I want to point out is that the compliance rate wasn't perfect in both groups either,” which might also have helped explain the lack of benefit with EDTA, she noted. “About 78% of patients completed half the recommended infusions [and] 68% completed the full course, so maybe it's possible a full treatment regimen would have been needed to see a significant effect.”

Moreover, Baron continued, “we know that pharmacologic therapies have come a really long way over the last 20 years. We've got aggressive lipid lowering, we've got primary PCI rates that are high, we have all the new antidiabetic agents including SGLT2 inhibitors, and so I do wonder—similar to what we saw in REDUCE-AMI with beta-blockers—whether maybe the additional therapeutics that we have to treat cardiovascular disease now might have overcome the benefit that chelation therapy is able to offer.”

Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA), was unmoved by the environmental lead hypothesis, telling TCTMD: “I do not think that a 40% lowering of lead levels in the US population is a cogent explanation as to why the therapeutic effects were not seen in this trial. If that were so, then the control arm in the TACT2 trial would have a lower event rate than the control arm in the diabetic subgroup of the TACT1 trial, but they were virtually identical: 40% in TACT2 versus 37% or thereabouts in the TACT1 trial.”

The most likely explanation for the null results is also the simplest one, he said. “Subgroup analyses, while tempting, are often treacherous; however, the investigators need to be congratulated for doing the right thing. They did not declare a win on the results of a subgroup analysis in TACT1, they considered it hypothesis-generating, they persevered with this hypothesis, got the funding going, and conducted the trial. This is how science should progress, even though the results were disappointing.”