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Chelation therapy to remove potentially toxic levels of lead from the blood was not associated with a reduction in cardiovascular events in post-myocardial infarction (MI) patients with diabetes in the TACT2 trial. 

The trial was conducted to try to confirm results of a previous study, the TACT trial, which had shown a reduction in cardiovascular events with edetate disodium chelation therapy (EDTA) in post-MI patients, with a particularly marked effect in those with diabetes.

Chief investigator of the TACT2 trial, Gervasio Lamas, MD, chair of medicine at Mount Sinai Medical Center in Miami, Florida, suggested that the different results from the TACT and TACT2 trials might have been due to lower blood levels of lead in the patients enrolled in the new trial, a reflection of the improved public health interventions (eg, the elimination of leaded gasoline) that have successfully reduced lead exposure in most developed countries over the past several decades. 

He pointed out that from 2003-2010, when the first TACT trial was ongoing, blood lead levels in the US averaged 17 mcg/L. Due to public health interventions, blood lead levels from 2015-2020 (when TACT2 was being conducted) averaged 10 mcg/L — a 41% drop. And in the TACT2 population, blood lead levels were even lower at baseline at 9 mcg/L. 

"So, my hypothesis is that US/Canadian blood levels have markedly dropped since 2003, reducing the potential therapeutic impact of further lowering blood lead levels," Lamas said. 

He concluded that: "TACT2 does not support the use of EDTA chelation for risk reduction in stable post-MI patients with diabetes in the US or Canada."

But he added: "If we had to do this over again, I think we could target patients with higher lead levels. If we look at lead levels worldwide, we see that in the developed world, lead levels are in the range of around 10 mcg/L, but in the developing world, lead levels are often above 60 mcg/L." 

Lamas presented the TACT2 study today at the American College of Cardiology's Annual Scientific Session in Atlanta.

Discussing the study at the late-breaking clinical trials session, Richard Chazal, MD, medical director of the Heart and Vascular Institute, Lee Memorial Health System, Fort Myers, Florida, thanked Lamas for conducting this trial to clarify the issue of whether chelation therapy could be beneficial in post-MI patients. 

"This can be a perplexing problem when patients ask us about this therapy, especially as FDA guidelines express some ambiguity, pointing out that this therapy is not FDA approved for this indication, but the TACT trial had suggested a signal," Chazal noted. 

Also commenting on the study at an ACC press conference, Suzanne Baron, MD, Massachusetts General Hospital, Boston , suggested other factors that may have contributed to the neutral result, including a "less than perfect" compliance rate, with 68% of patients completing the full course of chelation infusions; and the fact that pharmacological therapy had advanced considerably in the years between the two trials, which may have overcome the benefit that chelation could offer. 

In his presentation, Lamas explained that l ead and cadmium are ubiquitous environmental pollutants and recognized risk factors for atherosclerosis. EDTA is an avid lead and cadmium chelator and promotes their urinary elimination.

The previous TACT trial, conducted from 2003-2012, randomized 1702 patients with a prior MI to placebo or EDTA infusions, and found that cardiovascular events were reduced in the EDTA group (hazard ratio [HR], 0.82, P =.035) with a marked effect size (HR, 0.59, P =.0002) in patients with concomitant diabetes.

The aim of TACT2 was to try to replicate the TACT results in post-MI patients with diabetes, and measure the effect of repeated EDTA infusions on blood lead and urine cadmium.

The trial had a factorial design testing both EDTA and high dose oral multivitamins and minerals vs corresponding placebos. The current presentation focuses on the EDTA part of the study only. 

The trial randomized 1000 post-MI patients with diabetes to 40 weekly EDTA or placebo infusions. Minimum follow-up was 2.5 years, and median follow-up was 48 months.

Results showed that the EDTA chelation produced a 60% reduction in blood lead levels, and no safety issues were seen.

However, the EDTA infusions did not result in a significant clinical benefit on primary or secondary endpoints or on all-cause mortality.

The primary endpoint — the cumulative incidence of time to first event of MI, stroke, hospitalization for unstable angina, coronary revascularization, or death from any cause — showed a hazard ratio of 0.93 with EDTA (95% CI, 0.76 - 1.16), with a P value of. 53. 

There was also no difference in the results in various subgroups. 

Lamas noted that, in addition to the lower lead levels in the TACT2 population, patients in the second study also had more advanced diabetes and more severe associated health impacts than those in the first TACT trial, reducing the trial's ability to meaningfully affect clinical outcomes.

He suggested, however, that the study's findings in terms of overall lead reduction could still be relevant for informing health interventions in the majority of the world where lead exposure is more common.

"Our method of treatment was effective at reducing lead, even in patients starting with low lead levels, and it was safe," Lamas said. 

"In most countries outside of North America and western Europe, lead remains a serious cardiovascular and neurological problem," he said. "This study may be more relevant to those areas of the world, but this is a hypothesis that requires further study."

The TACT2 study was funded by the US National Institutes of Health. Lamas reports no disclosures.