Search

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.

Background: The NIH-funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stable patients age ≥50 who were ≥6 months post myocardial infarction to 40 infusions of an edetate disodium-based regimen or placebo. In 633 patients with diabetes, edetate disodium significantly reduced the primary composite endpoint of mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.001). The principal secondary endpoint of a composite of cardiovascular death, myocardial infarction, or stroke was also reduced (HR 0.60, 95% CI 0.39-0.91, p = 0.017). It is unknown if the treatment effect differs by diabetes therapy., Methods: We grouped the subset of 633 patients with diabetes according to glucose-lowering therapy at time of randomization. The log-rank test was used to compare active therapy versus placebo. All treatment comparisons were performed using 2-sided significance tests at the significance level of 0.05 and were as randomized. Relative risks were expressed as HR with associated 95% CI, calculated using the Cox proportional hazards model., Results: There were 162 (25.7%) patients treated with insulin; 301 (47.5%) with oral hypoglycemics only; and 170 (26.8%) receiving no pharmacologic treatment for diabetes. Patients on insulin reached the primary endpoint more frequently than patients on no pharmacologic treatment [61 (38%) vs 49 (29%) (HR 1.56, 95% CI 1.07-2.27, p = 0.022)] or oral hypoglycemics [61 (38%) vs 87 (29%) (HR 1.46, 1.05-2.03, p = 0.024)]. The primary endpoint occurred less frequently with edetate disodium based therapy versus placebo in patients on insulin [19 (26%) vs 42 (48%) (HR 0.42, 95% CI 0.25-0.74, log-rank p = 0.002)], marginally in patients on oral hypoglycemics [38 (25%) vs 49 (34%) (HR 0.66, 95% CI 0.43-1.01, log-rank p = 0.041)], and no significant difference in patients not treated with a pharmacologic therapy [23 (25%) vs 26 (34%) (HR 0.69, 95% CI 0.39-1.20, log-rank p = 0.225)]. The interaction between randomized intravenous treatment and type of diabetes therapy was not statistically significant (p = 0.203)., Conclusions: Edetate disodium treatment in stable, post-myocardial infarction patients with diabetes suggests that patients on insulin therapy at baseline may accrue the greatest benefit., Clinical Trial Registration: clinicaltrials.gov identifier: http://clinicaltrials.gov/ct2/show/NCT00044213?term=TACT&rank=7 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213., Competing Interests: Declaration of competing interest There are no relevant conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Approximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions., Research Design and Methods: The multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina., Results: The median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30-0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052)., Conclusion: Atherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)