Edetate Disodium-Based Chelation for Patients With a Previous Myocardial Infarction and Diabetes: TACT2 Randomized Clinical Trial

Abstract

Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)-based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI).

Objective: To replicate the finding of TACT in individuals with diabetes and previous MI.

Design, setting, and participants: A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons.

Interventions: Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study.

Main outcomes and measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion.

Results: Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P = .53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 μg/L at baseline to 3.46 μg/L at infusion 40 (P < .001). Corresponding levels in the placebo group were 9.3 μg/L and 8.7 μg/L, respectively.

Conclusions and relevance: Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI.

Trial registration: ClinicalTrials.gov Identifier: NCT02733185.

Figure 1.. Screening, Randomization, and Follow-Up of Participants in the Trial to Assess Chelation Therapy 2 Study

EDTA indicates edetate disodium; MI, myocardial infarction. ^aSee eTable 1 in Supplement 3 for additional reasons for exclusion. ^bParticipants were randomly assigned by group to receive either high-dose oral multivitamins and multiminerals or matching placebo caplets to be taken twice a day after the infusion part of the study for the 60-month follow-up. ^cParticipants were considered to have completed the study if they did not die, were not lost to follow-up, and did not withdraw consent. ^dLost to follow-up is defined as no contact within 12 months of the end of study, which is defined as the 5-year informed consent expiration date or the administrative end of the study. The last contact is defined as the last known alive date. ^eAll randomized participants who received at least 1 infusion are included in the primary analysis population.

Figure 2.. Cumulative Incidence of Time to First Event

Beyond month 54 for each panel, the sample size for number at risk is lower than meaningful; therefore, the x-axis is displayed to 54 months. The hazard ratios (HRs) comparing chelation infusion vs placebo infusion and P value are from Cox proportional hazards regression with adjustment of oral multivitamins and multiminerals group, age, time-varying age (panels A and B), sex, and baseline insulin use. A hazard ratio of less than 1 indicates a benefit with chelation compared with placebo. Events occurring after withdrawal of consent or informed consent expiration were censored. A death date after withdrawn consent or informed consent expiration (obtained from a public data source) is considered an event (panel C).

Figure 3.. Preinfusion Metal Levels at Baseline and Infusion Period

Five observations in panel B (>10 μg/g of creatinine) were not included. The change from baseline to immediately prior to the 40th infusion between chelation and placebo was tested using the Wilcoxon rank-sum test. The y-axes and x-axes were offset to display both lines. The y-axes are on logarithmic scales. The length of the boxes represents the IQR (the distance between the 25th and 75th percentiles). The triangle in the box interior represents the group mean; the horizontal line in the box interior, group median; whiskers 1.5 × IQR; and small circles, suspected outliers.