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<reference>
Trial to Assess Chelation Therapy 2 - American College of Cardiology

Amit Saha, MD

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Trial to Assess Chelation Therapy 2 - TACT2

Sep 18, 2024

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A

A

Author/Summarized by Author:

Amit Saha, MD

Summary Reviewer:

Dharam J. Kumbhani, MD, SM, FACC

Trial Sponsor:

National Institutes of Health

Date Presented:

04/07/2024

Date Published:

08/14/2024

Date Updated:

09/18/2024

Original Posted Date:

04/07/2024

References

Contribution To Literature:

Highlighted text has been updated as of September 18, 2024.

The TACT2 trial showed that in patients with prior MI and diabetes, intravenous chelation therapy with EDTA was not associated with a reduced risk of death or cardiovascular events compared with placebo.

Description:

The goal of the trial was to determine the potential clinical benefit of the chelating agent edetate disodium (EDTA) in older adults with a history of myocardial infarction (MI) and diabetes mellitus (DM).

Study Design

Randomized

Double-blind

Multicenter (USA/Canada)

Factorial

Patients with a history of MI and DM were randomized in a 1:1 fashion to receive 40 weekly intravenous infusions of 500 mL EDTA (n = 483) or saline/1.2% dextrose placebo (n = 476). The EDTA infusion included up to 3 grams of EDTA based on renal function. Each arm was also randomized in a 1:1 fashion to receive an oral high-dose vitamin and mineral supplement or placebo (results not reported here).

Total number of enrollees:
959

Duration of follow-up:
5 years

Median patient age: 67 years

Percentage female: 27%

Inclusion criteria:

Men or postmenopausal women age ≥50 years

MI >6 weeks prior

DM history, defined by use of insulin or oral diabetes therapy, fasting blood glucose >125 mg/dL, or glycated hemoglobin (HbA
1c
) ≥6.5%

Exclusion criteria:

Serum creatinine >2.0 mg/dL

HbA
1c
>11.0%

Coronary or peripheral revascularization
or heart failure admission
<6 months prior

Intravenous or oral chelation therapy <5 or <2 years prior, respectively

Aminotransferase levels >2 times upper limit of normal

Cigarette smoking
<3 months prior

Other salient features/characteristics:

Median time since qualifying MI: 5 years

Median HbA
1c
:
7.2
%

Median low-density lipoprotein cholesterol (LDL-C):
73
mg/dL

Median blood lead level: 9.2 µg/L

Mean urine cadmium level: 0.30 µg/g creatinine

Principal Findings:

The primary outcome, composite of time to all-cause death, MI, stroke, coronary revascularization, or hospitalization for unstable angina, for EDTA vs. placebo, was:
35.6% vs. 35.7%,
hazard ratio (HR) 0.93 (95% confidence interval [CI] 0.76-1.16), p = 0.53

Secondary outcomes for EDTA vs. placebo:

Cardiovascular death, MI, or stroke: 18.4% vs. 19.7%, HR 0.89 (95% CI 0.66-1.19)

All-cause death:
17.4% vs. 17.6%,
HR 0.96 (95% CI 0.71-1.30)

Change in
median
blood lead level from baseline: -5.5 vs. -0.6 µg/L, p < 0.001

Change in
median
urine cadmium level from baseline: -0.04 vs. 0 µg/g creatinine, p = 0.15

Compliance with all 40 infusions, EDTA vs. placebo, was: 68% vs. 67%.

Interpretation:

The original TACT trial demonstrated a modest reduction in death and cardiovascular events associated with EDTA, driven largely by lower rates of coronary revascularization. Given the historically contested reception to chelation therapy for atherosclerotic disease, TACT2 was designed to replicate its predecessor’s findings in patients with DM, who derived the greatest benefit compared with placebo in the original study. Surprisingly, no difference in clinical outcomes was observed in this cohort despite similar adherence over a similar follow-up period.

The authors note that this may reflect a smaller potential treatment effect size as blood lead levels in the US and Canada have continued to decrease since the TACT cohort was studied and were even lower in the study cohort compared with contemporary population data. Moreover, a greater proportion of patients in TACT2 were not only taking statins or antiplatelet therapies but also sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, agents with proven cardiovascular benefits that were not available during TACT. The current findings therefore do not support chelation therapy for post-MI patients with DM. Given the outsized benefit originally seen with TACT in this subset further implies that chelation therapy is not indicated regardless of DM status after MI.

References:

Lamas GA, Anstrom KJ, Navas-Acien A, et al. Edetate Disodium–Based Chelation for Patients With a Previous Myocardial Infarction and Diabetes: TACT2 Randomized Clinical Trial.
JAMA
2024;332:794-803
.

Presented by Dr. Gervasio A. Lamas at the American College of Cardiology Annual Scientific Session (ACC.24), Atlanta, GA, April 7, 2024.

Clinical Topics:

Atherosclerotic Disease (CAD/PAD),
Acute Coronary Syndromes,
Diabetes and Cardiometabolic Disease

Keywords:

ACC24,
ACC Annual Scientific Session,
Chelation Therapy,
Coronary Artery Disease,
Diabetes Mellitus

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</reference>

<statements>
1. This modest benefit was driven primarily by a reduction in coronary revascularization procedures
2. Despite these findings, the cardiology community remained cautious due to significant trial limitations
3. The primary composite endpoint occurred in 35.6% of the chelation group compared with 35.7% of the placebo group (\(\text{adjusted HR } 0.93\), \(95\%\text{ CI } [0.76, 1.16]\), \(p=0.53\))
4. The key secondary composite endpoint of cardiovascular death, MI, or stroke showed no significant difference between treatment arms (18.4% vs. 19.7%, \(\text{HR } 0.89\), \(95\%\text{ CI } [0.66, 1.19]\))
5. All-cause mortality was equivalent between groups (17.4% vs. 17.6%, \(\text{HR } 0.96\), \(95\%\text{ CI } [0.71, 1.30]\))
6. A substantial proportion of TACT2 patients were treated with high-intensity statins, dual antiplatelet therapy, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists
7. These therapies provide anti-inflammatory and vascular protection that may attenuate any incremental benefit from metal clearance
8. The median baseline blood lead level in TACT2 participants was under \(1.0\ \mu\text{g/dL}\) (\(9.03\ \mu\text{g/L}\))
9. Extracting metals below these low ambient thresholds yields minimal biological effect, indicating that chelation cannot prevent cardiovascular events when population exposure has already dropped below pathogenic levels
10. Finally, the prominent effect seen in the TACT diabetic subgroup likely reflected statistical noise and regression to the mean rather than a true biological difference, an interpretation reinforced by the neutral results in TACT2
11. Primary Result & Hazard Ratio: **Neutral:** \(\text{HR } 0.93\) (\(95\%\text{ CI } [0.76, 1.16]\), \(p=0.53\))
12. In TACT2, only 68% of participants completed the full 40-infusion regimen, illustrating the high participant burden, clinical resource allocation, and direct medical costs of this strategy
13. Modern guideline-directed secondary prevention, coupled with broad secular declines in population lead exposure, has eliminated any residual benefit chelation might have offered
</statements>

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