Possible differential benefits of edetate disodium in post-myocardial infarction patients with diabetes treated with different hypoglycemic strategies in the Trial to Assess Chelation Therapy (TACT)

Abstract

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: https://ichgcp.net/clinical-trials-registry/NCT00044213?term=TACT&rank=7 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213.

Keywords: Chelation; Diabetes; Edetate disodium; Insulin; Myocardial infarction.

Conflict of interest statement

Declaration of competing interest There are no relevant conflicts of interest.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Kaplan-Meier curves comparing edetate disodium chelation infusion groups versus placebo with respect to the primary endpoint in patients with diabetes in the three different subgroups according to their diabetes treatment.

Figure 1:

Kaplan-Meier curves comparing edetate disodium chelation infusion groups versus placebo with respect to the primary endpoint in patients with diabetes in the three different subgroups according to their diabetes treatment.

Figure 1:

Kaplan-Meier curves comparing edetate disodium chelation infusion groups versus placebo with respect to the primary endpoint in patients with diabetes in the three different subgroups according to their diabetes treatment.