Key Points:
- EDTA is a highly effective chelator of the ubiquitous pollutants lead and cadmium, both of which are associated with elevated cardiovascular risk.
- The first TACT study found that the subgroup of patients with prior MI and diabetes randomized to EDTA had markedly lower cardiovascular event rates compared to placebo.
- The current TACT2 study sought to replicate those results, and randomized 1000 post-MI diabetic patients to EDTA, high-dose oral multivitamins, or corresponding placebos.
- Contrary to the signal seen in the first TACT study, TACT2 found no significant differences in the primary composite cardiovascular endpoint between the EDTA and placebo arms.
Both lead and cadmium exposure is associated with increased cardiovascular risk. Edetate disodium (EDTA) chelates both and promotes their urinary excretion. The first Trial to Assess Chelation Therapy (TACT), performed from 2003-2012, randomized post-myocardial infarction (MI) patients to EDTA or placebo and found a significant reduction in overall cardiovascular events in the EDTA group, with an especially large effect size in the those with concomitant diabetes (HR 0.59, p=0.0002). The purpose of TACT2 was to re-evaluate the effect of EDTA in this specific population in a modern cohort of patients.
On April 7, 2024, the results of the “The Effect of Edetate Disodium-based Chelation on Cardiovascular Events in Patients with a Prior Myocardial Infarction and Diabetes: The TACT2 Randomized Trial” were presented at ACC Scientific Sessions 2024 as a Late Breaking Clinical Trial with simultaneous publication in Circulation.
This double-blind factorial trial randomized adults aged 50 or older with diabetes and prior MI in a 1:1:1:1 fashion to 40 weekly EDTA infusions, oral multivitamins and minerals, placebo EDTA, or placebo multivitamins, though the current presentation focused only on EDTA vs placebo. Those who were active smokers or had serum creatinine>=2 mg/dl were excluded. The primary endpoint was a composite of time to the first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina, assessed using a Cox proportional hazards regression model.
Primary analyses were reported for the modified intention to treat population that excluded 41 of the 1000 randomized patients who never received any infusion. For the 959 analyzed patients, the median age was 67, about a quarter were female, and 60% were white; the median time from MI to randomization was 5 years. The median follow up was 48 months. About 70% of both EDTA and placebo arms received all 40 infusions.
There was no significant difference between the EDTA and placebo group for the primary outcome (HR 0.95 [95% CI 0.76-1.16], p = 0.53) or time to all-cause mortality (HR 0.96 [0.71-1.30]). There were also no significant differences in any of the subgroup analyses for the primary endpoint. There was a significant decrease in lead levels of over 60% in the EDTA group from baseline compared to placebo, however there was no difference in cadmium levels.
Dr. Gervasio A. Lamas of Columbia University concluded: “TACT2 does not support the use of edetate disodium (EDTA) chelation for risk reduction stable post MI patients with diabetes.” One potential explanation for the discrepancy between TACT and TACT2 offered by the investigators was that the overall blood lead level in the US population dropped by 35% between the two study periods, which may have reduced the potential therapeutic impact of EDTA.