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

Does therapy with edetate disodium (EDTA)–based chelation reduce major adverse cardiovascular events compared with placebo infusions among patients with diabetes and prior myocardial infarction (MI)? EDTA-based chelation did not reduce major adverse ...

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JAMA
. 2024 Aug 14;332(10):794–803. doi:
10.1001/jama.2024.11463

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Edetate Disodium–Based Chelation for Patients With a Previous Myocardial Infarction and Diabetes

TACT2 Randomized Clinical Trial

Gervasio A Lamas

Gervasio A Lamas
,
MD

1
Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, Florida

Find articles by
Gervasio A Lamas

1,
✉
,
Kevin J Anstrom

Kevin J Anstrom
,
PhD

2
Gillings School of Global Public Health, University of North Carolina, Chapel Hill

Find articles by
Kevin J Anstrom

2
,
Ana Navas-Acien

Ana Navas-Acien
,
MD, PhD

3
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York

Find articles by
Ana Navas-Acien

3
,
Robin Boineau

Robin Boineau
,
MD, MA

4
National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland

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Robin Boineau

4
,
Hayley Nemeth

Hayley Nemeth
,
MS

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

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Hayley Nemeth

5
,
Zhen Huang

Zhen Huang
,
MS

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

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Zhen Huang

5
,
Jun Wen

Jun Wen
,
MS

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

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Jun Wen

5
,
Yves Rosenberg

Yves Rosenberg
,
MD, MPH

6
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

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Yves Rosenberg

6
,
Mario Stylianou

Mario Stylianou
,
PhD

6
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

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Mario Stylianou

6
,
Teresa L Z Jones

Teresa L Z Jones
,
MD

7
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

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Teresa L Z Jones

7
,
Bonnie R Joubert

Bonnie R Joubert
,
PhD, MPH

8
National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina

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Bonnie R Joubert

8
,
Qilu Yu

Qilu Yu
,
PhD

4
National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland

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Qilu Yu

4
,
Regina M Santella

Regina M Santella
,
PhD

3
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York

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Regina M Santella

3
,
Ana C Mon

Ana C Mon
,
MPH

1
Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, Florida

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Ana C Mon

1
,
Francisco Ujueta

Francisco Ujueta
,
MD, MS

1
Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, Florida

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Francisco Ujueta

1
,
Esteban Escolar

Esteban Escolar
,
MD

1
Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, Florida

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Esteban Escolar

1
,
David M Nathan

David M Nathan
,
MD

9
Massachusetts General Hospital Diabetes Research Center, Harvard Medical School, Boston

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David M Nathan

9
,
Vivian A Fonseca

Vivian A Fonseca
,
MD

10
Tulane University School of Medicine, New Orleans, Louisiana

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Vivian A Fonseca

10
,
Y Wady Aude

Y Wady Aude
,
MD, MPH

11
DHR Health Heart Institute, McAllen, Texas

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Y Wady Aude

11
,
Jonathan K Ehrman

Jonathan K Ehrman
,
PhD

12
Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan

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Jonathan K Ehrman

12
,
Thomas Elliott

Thomas Elliott
,
MBBS

13
BC Diabetes Research Institute, Vancouver, British Columbia, Canada

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Thomas Elliott

13
,
Rakesh Prashad

Rakesh Prashad
,
MD

14
Ocala Research Institute, Ocala, Florida

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Rakesh Prashad

14
,
Eldrin F Lewis

Eldrin F Lewis
,
MD, MPH

15
Stanford University School of Medicine, Palo Alto, California

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Eldrin F Lewis

15
,
Renato D Lopes

Renato D Lopes
,
MD, MHS, PhD

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

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Renato D Lopes

5
,
Michael E Farkouh

Michael E Farkouh
,
MD, MSc

16
University of Toronto, Toronto, Ontario, Canada

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Michael E Farkouh

16
,
Anne-Marie Elliott

Anne-Marie Elliott
,
BA

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

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Anne-Marie Elliott

5
,
Jonathan D Newman

Jonathan D Newman
,
MD, MPH

17
New York University School of Medicine, New York

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Jonathan D Newman

17
,
Daniel B Mark

Daniel B Mark
,
MD, MPH

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

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Daniel B Mark

5
,
for the TACT2 Investigators

Author information

Article notes

Copyright and License information

1
Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, Florida

2
Gillings School of Global Public Health, University of North Carolina, Chapel Hill

3
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York

4
National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland

5
Duke Clinical Research Institute, Duke University, Durham, North Carolina

6
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

7
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

8
National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina

9
Massachusetts General Hospital Diabetes Research Center, Harvard Medical School, Boston

10
Tulane University School of Medicine, New Orleans, Louisiana

11
DHR Health Heart Institute, McAllen, Texas

12
Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan

13
BC Diabetes Research Institute, Vancouver, British Columbia, Canada

14
Ocala Research Institute, Ocala, Florida

15
Stanford University School of Medicine, Palo Alto, California

16
University of Toronto, Toronto, Ontario, Canada

17
New York University School of Medicine, New York

Group Information:
The TACT2 Investigators appear in the
Supplement 4
.

Accepted for Publication:
May 28, 2024.

Published Online:
August 14, 2024. doi:
10.1001/jama.2024.11463

✉
Corresponding Author:
Gervasio A. Lamas, MD, Mount Sinai Medical Center, 4300 Alton Rd, Ste 2070A, Miami Beach, FL 33140 (
gervasio.lamas@msmc.com
).

Author Contributions:
Dr Lamas had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design:
Lamas, Anstrom, Navas-Acien, Boineau, Rosenberg, Stylianou, Jones, Yu, Mon, Ujueta, Escolar, Nathan, Lewis, Farkouh, Newman, Mark.

Acquisition, analysis, or interpretation of data:
Lamas, Anstrom, Navas-Acien, Boineau, Nemeth, Huang, Wen, Rosenberg, Stylianou, Jones, Joubert, Yu, Santella, Ujueta, Fonseca, Aude, Ehrman, T. Elliott, Prashad, Lewis, Lopes, A.M. Elliott, Newman, Mark.

Drafting of the manuscript:
Lamas, Anstrom, Navas-Acien, Boineau, Nemeth, Stylianou, Jones, Yu, Santella, Ujueta, Newman.

Critical review of the manuscript for important intellectual content:
Lamas, Anstrom, Navas-Acien, Boineau, Huang, Wen, Rosenberg, Stylianou, Jones, Joubert, Yu, Mon, Ujueta, Escolar, Nathan, Fonseca, Aude, Ehrman, T. Elliott, Prashad, Lewis, Lopes, Farkouh, A.M. Elliott, Newman, Mark.

Statistical analysis:
Anstrom, Navas-Acien, Nemeth, Huang, Wen, Stylianou, Yu, Ujueta.

Obtained funding:
Lamas, Anstrom, Mark.

Administrative, technical, or material support:
Lamas, Navas-Acien, Boineau, Rosenberg, Jones, Santella, Mon, Escolar, Fonseca, T. Elliott, Prashad, Lewis, A.M. Elliott.

Supervision:
Lamas, Navas-Acien, Boineau, Rosenberg, Joubert, Yu, Escolar, Nathan, Fonseca, Aude, Lewis.

Other - interpretation of results:
Lamas, Anstrom, Mark.

Conflict of Interest Disclosures:
Dr Navas-Acien reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Dr Fonseca reported receiving grants from Novo Nordisk paid to Tulane outside the submitted work; having a patent pending for the BRAVO risk engine for predicting diabetes complications; receiving consulting and lectures fees from Asahi, Bayer, Abbott, Boehringer Ingelheim, Corcept, Eli Lilly, AbbVie; having stock options for Mellitus Health and BRAVO4Health; and owning stock from Amgen and Abbott. Dr Lopes reported receiving grants from Amgen, Bristol Myers Squibb, GSK, Medtronic, Pfizer, and Sanofi and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Novo Nordisk, and Pfizer. Dr Farkouh reported receiving grants from Novo Nordisk, AstraZeneca, Novartis, and Amgen and personal fees from Otitopic and Sanofi. Dr Newman reported receiving grants from the NIH outside the submitted work. Dr Mark reported receiving grant support from HeartFlow, Inc, Merck, and Novo Nordisk outside the submitted work; consulting fees from CeleCor, Novartis, and Boehringer Ingelheim outside the submitted work; and honoraria from Elsevier outside the submitted work. No other disclosures were reported.

Funding/Support:
The National Center for Complementary and Integrative Health, the National Heart, Lung, and Blood Institute, the National Institute for Diabetes Digestive and Kidney Diseases, and the National Institute of Environmental Health Sciences (NIEHS) provided funding and supervision for TACT2, under award numbers: 1UG3AT009149, 5UH3AT009149, 2UH3AT009150, 5R01AT009273, and 2U24AT009150. The Trace Metals and Biorepository Center at Columbia University is also supported by grants P30ES009089 and P42ES033719 from the NIEHS and P30CA013696 from the National Cancer Institute.

Role of the Funder/Sponsor:
The study was funded through a Cooperative Agreement mechanism. As such, the NIH had a collaborative role in the design, analysis, interpretation of data, review, and approval of the manuscript. The NIH had limited role regarding data collection and site management.

Group Information:
The TACT2 Investigators appear in
Supplement 4
.

Disclaimer:
The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Department of Health and Human Services.

Data Sharing Statement:
See
Supplement 5
.

Additional Contributions:
The Centers for Disease Control and Prevention performed metal analyses on biological specimens from TACT2 participants.

✉
Corresponding author.

Received 2024 Feb 26; Accepted 2024 May 28; Issue date 2024 Sep 10.

Copyright 2024 American Medical Association. All Rights Reserved.

PMC Copyright notice

PMCID: PMC11325247 PMID:
39141382

See commentary "
Chelation Therapy Following Myocardial Infarction.
" with doi: 10.1001/jama.2024.13549.

Key Points

Question

Does therapy with edetate disodium (EDTA)–based chelation reduce major adverse cardiovascular events compared with placebo infusions among patients with diabetes and prior myocardial infarction (MI)?
Findings

EDTA-based chelation did not reduce major adverse cardiovascular events compared with placebo infusion, with a hazard ratio of 0.93 (95% CI, 0.76-1.16;
P
= .53). Chelation infusions did reduce the median blood lead levels from 9.0 μg/L at baseline to 3.5 μg/L at infusion 40 (
P
< .001).
Meaning

Among patients with diabetes and prior MI, EDTA-based chelation decreased median blood lead levels by 61% from baseline but did not reduce major adverse cardiovascular events.
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

This randomized clinical trial assesses whether edetate disodium–based chelation infusions decrease cardiovascular disease events compared with placebo among patients with diabetes and prior myocardial infarction.
Introduction

In 2013, the Trial to Assess Chelation Therapy (TACT) reported an 18% relative risk reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA)–based infusions relative to placebo in patients who had experienced a myocardial infarction (MI).
1
In the subgroup of patients with diabetes, the primary composite event rate demonstrated a relative risk reduction of 41%.
2
Because the primary known biological activity of EDTA is to avidly chelate lead, cadmium, and other divalent cations,
3
,
4
,
5
toxic metal chelation was postulated to be the mechanism of benefit, a hypothesis supported by epidemiological studies linking chronic exposure to contaminant metals, especially lead and cadmium, in patients with CVD.
6
,
7
,
8
,
9
Worldwide analyses have estimated that more than 5.5 million CVD deaths in 2019 were attributable to low to moderate lead exposure.
10
Cadmium, likewise, is ubiquitous and atherogenic.
11
,
12
A recent scientific statement from the American Heart Association recognized lead, cadmium, and arsenic as risk factors for atherosclerosis.
13
This current study (TACT2) was designed to replicate its predecessor study but involving patients with diabetes and prior MI to assess the relationship between the expected prognostic benefits and the depletion of body stores of lead and cadmium with repeated EDTA infusions.
14
Methods

Overview

TACT2 was a multicenter, double-masked 2 × 2 factorial trial comparing the effect of 40 infusions of an EDTA-based solution with placebo infusions administered approximately weekly and comparing the effect of high doses of oral multivitamins and minerals with oral placebo (
Figure 1
). The present article describes the effects of chelation on the primary combined CVD end point. Details of the study protocol have been published.
14

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

Open in a new tab

EDTA indicates edetate disodium; MI, myocardial infarction.

a
See eTable 1 in
Supplement 3
for additional reasons for exclusion.

b
Participants 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.

c
Participants were considered to have completed the study if they did not die, were not lost to follow-up, and did not withdraw consent.

d
Lost 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.

e
All randomized participants who received at least 1 infusion are included in the primary analysis population.
Supervision

Institutional review boards of participating sites approved the final protocol and provided ongoing oversight (
Supplement 1
). All participants provided written informed consent. The data and safety monitoring board (DSMB) members were appointed by the National Institutes of Health (NIH). The board members developed a charter with predefined times to recommend continuation or cessation of the trial to the NIH and supervised the conduct of the trial. The statistical analysis plan is available in
Supplement 2
.
Trial Organization

The clinical coordinating center at Mount Sinai Medical Center (Miami Beach, Florida) recruited sites and coordinated central pharmacy activities. The Duke Clinical Research Institute (DCRI) served as the data coordinating center and performed site and data management and statistical analyses. The Mailman School of Public Health at Columbia University served as the trace metals and biorepository center and coordinated the receipt of specimens from clinical sites and delivery of blood and urine to the Centers for Disease Control and Prevention for metal assays. Each clinical site was led by a licensed physician. Site personnel obtained informed consent, evaluated, randomized, enrolled, and infused participants according to the randomized assignment. Sites collected and entered data into the trial electronic data collection system (Medidata Rave EDC). Follow-up took place at the sites during the infusion phases and subsequently was transferred to the telephone-based DCRI participant research operations call center. This trial is reported following the Consolidated Standards of Reporting Trials (
CONSORT
) reporting guideline.
Masking

The clinical sites, clinical coordinating center, and trace metals and biorepository center were fully masked to treatment assignment. A masked statistical team was responsible for all interactions with study staff. An unmasked statistical team received and analyzed unmasked data for presentation to the DSMB on a predetermined schedule. An independent unmasked team at the NIH worked with the DSMB and the unmasked DCRI team.
Study Population

Eligible participants were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment (
Table 1
). Participants were excluded (eTable 1 in
Supplement 3
) if they were women of childbearing potential, had a serum creatinine level greater than 2.0 mg/dL, blood pressure greater than 160/100 mm Hg, cigarette smoking within 3 months, heart failure hospitalization within 6 months, or inability to tolerate 500-mL infusions weekly. Race and ethnicity were self-reported. Participants were enrolled at 88 sites, of which 14 (15.9%) commonly practiced chelation.
14

Table 1. Demographics and Baseline Clinical Characteristics in the Primary Analysis Population
a
.

Characteristic

EDTA chelation (n = 483)

Placebo infusion (n = 476)

Age, median (IQR), y

67 (60-72)

67 (61-72)

Sex, No. (%)

Female

137 (28.4)

121 (25.4)

Male

346 (71.6)

355 (74.6)

Race, No. (%)
b

American Indian or Alaska Native

1 (0.2)

4 (0.8)

Asian

25 (5.2)

27 (5.7)

Black or African American

51 (10.6)

43 (9.0)

Native Hawaiian or Other Pacific Islander

7 (1.4)

9 (1.9)

White

373 (77.2)

377 (79.2)

Multirace

4 (0.8)

2 (0.4)

Other

22 (4.6)

14 (2.9)

Ethnicity, No./total No. (%)

Hispanic or Latino

93/475 (19.6)

93/473 (19.7)

Not Hispanic or Latino

382/475 (80.4)

380/473 (80.3)

Medical history, No./total (%) or No. (%)
c

Type 1 diabetes

18 (3.7)

20 (4.2)

Type 2 diabetes

465 (96.3)

456 (95.8)

Time from diabetes diagnosis to randomization, median (IQR), y
d

14 (8-21)

14 (7-22)

Time from qualifying MI to randomization, median (IQR), y

5 (2-10)

5 (2-11)

Hypertension (requiring treatment)

442 (91.5)

440/475 (92.6)

Hypercholesterolemia
e

437/480 (91.0)

430/473 (90.9)

Any cardiac revascularization (CABG or PCI)

395/481 (82.1)

388/474 (81.9)

Complications of diabetes
f

204/482 (42.3)

228/473 (48.2)

Anterior MI

138 (28.6)

158 (33.2)

Congestive heart failure

110 (22.8)

86 (18.1)

Peripheral vascular disease

68/472 (14.4)

83/467 (17.8)

Stroke

49/480 (10.2)

42/474 (8.9)

Medications, No./total (%) or No. (%)

Aspirin, warfarin, or P2Y12 inhibitor

433 (89.6)

429/475 (90.3)

Statin

416 (86.1)

408 (85.7)

β-Blocker

376/482 (78.0)

386 (81.1)

ACE inhibitor or angiotensin receptor blocker

316 (65.4)

298 (62.6)

PCSK9 inhibitor

17/482 (3.5)

12/474 (2.5)

Insulin

236 (48.9)

212 (44.5)

Other oral agents

328 (67.9)

329/475 (69.3)

GLP-receptor agonist or SGLT-2 inhibitor

98 (20.3)

114/473 (24.1)

DPP-4 inhibitor

52 (10.8)

59/472 (12.5)

Other diabetes medications

31/476 (6.5)

34/471 (7.2)

No diabetes medications

27/480 (5.6)

25/475 (5.3)

Vitals

BMI, median (IQR)

31.7 (28.3-36.0)

31.7 (28.1-36.5)

Systolic blood pressure, mean (SD), mm Hg

131.9 (17.05)

133.4 (17.74)

Diastolic blood pressure, mean (SD), mm Hg

73.9 (9.97)

74.3 (10.71)

Laboratory examinations, median (IQR)
g

Fasting glucose, mg/dL

134.5 (110.0-166.0)

137.0 (114.0-177.0)

Hemoglobin A
1c
, %

7.2 (6.4-8.4)

7.3 (6.6-8.3)

Creatinine, mg/dL

1.0 (0.9-1.2)

1.0 (0.9-1.3)

Calculated eGFR, mL/min/1.73 m
2

68.6 (55.1-84.4)

68.9 (52.8-83.8)

HDL, mg/dL

41.0 (34.0-49.0)

41.0 (34.0-49.0)

LDL, mg/dL

73.0 (58.0-98.0)

71.0 (53.0-94.0)

Total cholesterol, mg/dL

146.0 (124.0-176.0)

142.0 (121.0-175.0)

Triglycerides, mg/dL

142.0 (102.0-215.0)

145.0 (104.0-221.0)

Lead (blood), μg/L

9.00 (6.14-14.00)

9.40 (6.40-14.00)

Cadmium (urine), μg metal/g creatinine
h

0.31 (0.17-0.52)

0.29 (0.18-0.51)

Open in a new tab

Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; CABG, coronary bypass graft; DPP, dipeptidyl peptidase; EDTA, edetate disodium; eGFR, estimated glomerular filtration rate; GLP, glucagon-like peptide; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention; SGLT, sodium-glucose cotransporter.

SI conversion factors: To convert creatinine from mg/dL to μg/L, multiply by 88.4; glucose from mg/dL to mmol/L, multiply by 0.0555; HDL, LDL, and total cholesterol from mg/dL to mmol/L, multiply by 0.0259; lead, from μg/L to μmol/L, multiply by 0.0483; and triglycerides from mg/dL to mmol/L, multiply by 0.0113.

a

Baseline data for all randomized patients regardless of infusion status is provided in eTable 3 in
Supplement 3
.

b

Race collected by selecting all that apply as reported by the participant. If multiple races were selected, participant is included in the multirace category.

c

Medical history is participant reported.

d

Year of diabetes diagnosis was collected. Day and month imputed as June 1 of the collected year.

e

Total cholesterol greater than 240 mg/dL; LDL greater than 130 mg/dL.

f

Laser or injection eye treatment for retinopathy, neuropathy, amputation, or hypoglycemia with help needed for treatment.

g

Extreme values have been investigated and confirmed by the study investigator. For reference ranges, refer to eTable 4 in
Supplement 3
.

h

Baseline metal levels (μg/g) corrected for urinary creatinine (μg of metal per g creatinine).

Treatments

An investigational new drug application for disodium EDTA for treatment of coronary artery disease had been approved by the US Food and Drug Administration in 2003. The refrigerated blinded active chelation and placebo solutions were prepared by a central pharmacy and were identical to the solutions used in TACT. Active infusions consisted of up to 3 g of disodium EDTA, adjusted based on estimated creatinine clearance; 7 g of ascorbic acid; 2 g of magnesium chloride; 100 mg of procaine hydrochloride; 2500 U of unfractionated heparin; 2 mEq of potassium chloride; 840 mg of sodium bicarbonate; 250 mg of pantothenic acid; 100 mg of thiamine; 100 mg of pyridoxine; and sterile water to make up 500 mL of solution. The identical-appearing placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total).

Infusions were administered through peripheral intravenous access over at least 3 hours. The target schedule was 40 total weekly infusions, with flexibility for longer intervals provided for vacations, for sick time, and during the COVID pandemic. During the infusion phase of the trial, all study participants received a daily low-dose vitamin regimen. The randomized oral vitamin regimen, composed of high-dose oral multivitamins and minerals or matching placebo caplets, was administered throughout the 60-month follow-up.
Follow-Up and Safety Monitoring

Patient monitoring during the infusion period included focused physical examinations and 4 blood draws. Participants were contacted to assess interval clinical events at 6 months and 12 months after randomization and continuing every 4 months for 5 years or until the end of the study (eTable 2 in
Supplement 3
for the trial evaluation schedule).
Outcomes

The primary end point was a composite of death from any cause, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The secondary end points included: individual elements of the primary composite end point, all-cause mortality, and a composite of cardiovascular mortality, MI, or stroke. A masked clinical events committee adjudicated all nonprocedural components of the primary and secondary end points. Coronary revascularizations were verified using medical records. Primary mechanistic end points included the change in blood lead and urine cadmium levels from baseline to the final infusion.
15
Prespecified Subgroup Analyses

Prespecified subgroups included women; racial and ethnic groups; persons older than 70 years; particularly high-risk participants based on history of anterior MI, peripheral artery disease, and pharmacological treatment of diabetes; and tertiles of blood lead and urine cadmium levels at baseline.
Statistical Analysis

Sample Size and Statistical Power

This study was designed as an event-driven trial with a planned sample size of 1200 randomized participants and a minimum follow-up of 12 months after the final infusion. The allocation ratio was 1:1:1:1 across the 4 treatment groups, defined as (1) active chelation and active vitamins, (2) placebo chelation and active vitamins, (3) active chelation and placebo vitamins, and (4) placebo chelation and placebo vitamins. A total of 282 primary end point events was estimated to provide 85% power assuming a hazard ratio (HR) of 0.70 for chelation vs placebo infusion. Because enrollment was slower than projected, mostly due to the COVID-19 pandemic, the final study enrollment was reduced to 1000 randomized participants, with the minimum follow-up period extended to 2.5 years.
Primary Analysis Population

The primary analyses are reported for the population who received at least 1 study infusion (n = 959).
Analysis Methods

The statistical analysis plan was finalized and approved by an NIH statistician prior to trial unmasking. Continuous variables are summarized as medians and IQRs along with means and standard deviations, as appropriate. Categorical variables are summarized in terms of frequencies and percentages. All statistical analyses used SAS version 9.4 or higher (SAS Institute Inc). The primary statistical comparison is based on the time from randomization to the first occurrence of any of the primary composite event components using the Cox proportional hazards regression model.
16
The Cox proportional hazards model included indicator variables for the active chelation and active oral multivitamins and minerals groups, and adjustment terms for age, sex, and use of insulin at baseline. The analyses of the secondary end points—(1) the composite of cardiovascular mortality, MI, or stroke and (2) time to all-cause mortality—were performed in the same manner as the primary analysis. Recurrent events were analyzed using the Andersen and Gill model.
17
Differences in the distributions of blood lead and urine cadmium levels from baseline to the 40th infusion were calculated in the chelation and placebo groups, and the medians and IQRs were plotted graphically. The change from baseline to immediately prior to the 40th infusion between chelation and placebo infusion was tested using the Wilcoxon rank-sum test. All statistical comparisons were performed using 2-sided significance tests.
Bayesian Sensitivity Analysis

A prespecified bayesian analysis estimated the posterior distribution of the primary outcome treatment effect size using at least 1 prior distribution for the effect of chelation vs placebo infusion in each of the following categories: skeptical, pessimistic, and optimistic.
18
All priors were assumed to follow a normal distribution and represented the log HR for the treatment effect from the Cox proportional hazards model. The skeptical (noninformative) prior for the log hazard ratio used a mean of 0. The pessimistic prior also used a mean of 0 but with a smaller variance. The 2 optimistic priors included the overall treatment effect from TACT (ie, HR, 0.82; 95% CI, 0.69-0.99)
1
and diabetes subgroup treatment effect from TACT (ie, HR, 0.59; 95% CI, 0.44-0.79).
2
The chelation treatment effect from the bayesian models was summarized using mean posterior HRs and associated 95% highest posterior density credible intervals. Posterior HRs less than 1 favored the chelation-based therapy.
Results

Between October 27, 2016, and December 31, 2021, 1000 individuals were randomly assigned either to EDTA-based chelation (n = 499) or to placebo infusions (n = 501). The last infusion was administered in December 2021, and the last patient follow-up took place on June 30, 2023 (
Figure 1
).

Baseline Characteristics

The median age of the population was 67 years (IQR, 60-72 years), 27% of whom were female and included 10% Black, 20% Hispanic, and 78% White individuals. Type 2 diabetes was present in 921 participants (96%;
Table 1
). Median duration of diabetes from diagnosis to randomization was 14 years (IQR, 7-22 years). The qualifying MI occurred a median of 5 years (IQR, 2-10 years) prior to enrollment, and 296 (31%) were anterior in location. Prior coronary revascularization had been performed in 783 of 955 participants (82%). Baseline medications included aspirin, warfarin, or P2Y12 inhibitors in 862 of 958 participants (90%), and statins in 824 (86%) of the entire analysis population. The median for hemoglobin A
1c
was 7.2% (IQR, 6.5%-8.3%); for low-density lipoprotein cholesterol, 73 mg/dL (IQR, 56-96 mg/dL); for high-density lipoprotein cholesterol, 41 mg/dL (IQR, 34-49 mg/dL); and for triglycerides, 144 mg/dL (IQR, 102-217 mg/dL). The median blood lead concentration was 9.2 μg/L (IQR, 6.3-14.0 μg/L) and urine cadmium levels, 0.30 μg (IQR, 0.18-0.52 μg) of metal per gram of creatinine.
Treatment Adherence

Randomized participants received a total of 31 615 infusions (15 787 chelation and 15 828 placebo). No infusions were unmasked during the study. Three hundred forty-one participants (68%) assigned to active chelation received all 40 infusions, and 391 (78%) received at least 20. In the placebo group, 336 participants (67%) received 40 infusions, and 393 (78%) received at least 20. Overall, 60 participants (22 chelation and 38 placebo groups, totaling 6%) withdrew consent during follow-up, and 62 participants (6%) were lost to follow-up (35 chelation and 27 placebo groups;
Figure 1
).
Outcome Events

The primary composite CVD outcome event in those receiving at least 1 infusion occurred in 172 participants (35.6%) in the chelation group and 170 participants (35.7%) in the placebo group (adjusted HR, 0.93; 95% CI, 0.76-1.16;
P
= .53;
Table 2
and
Figure 2
A; results for all randomized participants are provided in eTable 5 in
Supplement 3
). The Kaplan-Meier 5-year cumulative incidence estimates for the primary end point were 45.8% (95% CI, 39.9%-51.5%) for the chelation group and 46.5% (95% CI, 39.7%-53.0%) for the placebo group.

Table 2. Primary and Key Secondary End Points in the Primary Analysis Population.

No. (%) of participants with event

Difference (95% CI) [EDTA-placebo], %

Adjusted hazard ratio (95% CI)
a

P
value
b

EDTA chelation (n = 483)

Placebo infusion (n = 476)

Primary composite outcome

MI, stroke, hospitalization for unstable angina, coronary revascularization, or death from any cause

172 (35.6)

170 (35.7)

−0.1 (−6.2 to 6.0)

0.93 (0.76 to 1.16)
b

.53

Components of the primary outcome

MI

54 (11.2)

45 (9.5)

Stroke

14 (2.9)

16 (3.4)

Hospitalization for unstable angina

19 (3.9)

17 (3.6)

Coronary revascularization

35 (7.2)

39 (8.2)

Death from any cause

50 (10.4)

53 (11.1)

Secondary outcomes

MI, stroke, or death from cardiovascular causes

89 (18.4)

94 (19.7)

−1.3 (−6.3 to 3.7)

0.89 (0.66 to 1.19)
c

.42

All-cause mortality outcome

84 (17.4)

84 (17.6)

−0.3 (−5.1 to 4.6)

0.96 (0.71 to 1.30)
d

.78

Components of the secondary composite outcome

MI

55 (11.4)

51 (10.7)

Stroke

14 (2.9)

19 (4.0)

Death from cardiovascular causes

20 (4.1)

24 (5.0)

Open in a new tab

Abbreviation: EDTA, edetate disodium, MI, myocardial infarction.

a

Hazard ratio (chelation vs placebo infusion) is derived from Cox proportional hazards regression with adjustment of oral multivitamins and multiminerals group, age (and time-varying age), sex, and baseline insulin use. A hazard ratio of less than 1 indicates a benefit with chelation compared with placebo infusion. Events occurring after withdrawal of consent or informed consent expiration were censored. Participants with 2 or more events that occurred on the same day will show 1 event based on the following hierarchy: MI, stroke, hospitalization for unstable angina, coronary revascularization, and all-cause mortality.

b

Type I error (2-sided α = .05) is used as the threshold for hypothesis testing.
P
values are only displayed in the article if the prior end point is statistically significant.

c

The hazard ratio is derived from cause-specific Cox proportional hazards regression.

d

The hazard ratio is derived from Cox proportional hazards regression. A death date after withdrawn consent or informed consent expiration (obtained from a public data source) is considered an event with no time-varying age adjustment.

Figure 2. Cumulative Incidence of Time to First Event.

Open in a new tab

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).
None of the component CVD event rates differed between treatment groups (
Table 2
). 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;
Figure 2
B). 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;
Figure 2
C). There were 279 overall recurrent CVD events of any component of the composite end point in the chelation group, and 289 overall recurrent events in the placebo group; the Andersen-Gill model HR was 0.90 (95% CI, 0.72-1.12).
18
Prespecified sensitivity analyses to examine follow-up gaps, loss to follow-up, and consent withdrawal did not substantially affect the primary end point effect size (eTables 6-8 in
Supplement 3
).
Bayesian Sensitivity Analyses

With a skeptical prior (centered around a mean log HR of 0), the mean posterior HR for the primary composite end point was 0.95 (95% credible interval [CrI], 0.77 to 1.18; eTable 8, eFigure 1 in
Supplement 3
). With a pessimistic prior (also centered around a mean log HR of 0 but with a much smaller variance than the skeptical prior), the mean posterior HR was 0.98 (95% CrI, 0.86-1.12). The prespecified optimistic priors based on the overall TACT results (mean prior HR, 0.82) yielded a mean posterior HR of 0.88 (95% CrI, 0.76-1.01), whereas the prespecified mean prior based on the TACT diabetes subgroup (mean prior HR, 0.59) yielded a posterior HR of 0.81 (95% CrI, 0.68-0.96).
Effect of Chelation on Blood Lead and Urine Cadmium Levels

Median blood lead levels in the chelation group decreased from 9.0 μg/L (IQR, 6.1-13.6 μg/L ) preinfusion to 3.5 μg/L (IQR, 2.3-5.5 μg/L;
P
< .001) at the 40th infusion, for a 61% reduction (
Figure 3
). The curves showing blood lead levels by number of infusions suggest that by 20 infusions a steady-state blood lead–level reduction had been reached. There was no clinically relevant decrease in blood lead levels in the placebo group with a corresponding median of 9.3 μg/L (IQR, 6.4-14.0 μg/L) to 8.7 μg/L (IQR, 6.0-12.0 μg/L). There was no clinically relevant change over time in urine cadmium levels from preinfusion to the end of study in either the active chelation or placebo infusion treatment groups (
Figure 3
). However, urine cadmium levels 3 hours after infusion were increased by an average 561% (median, 1.64 μg/g) compared with preinfusion levels (median, 0.30 μg/g) throughout the chelation phase.

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

Open in a new tab

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.
Subgroup Analyses

There was no treatment heterogeneity in any of the prespecified subgroups including those defined by sex, race and ethnicity groups, age older than 70 years, and history of prior anterior MI or peripheral artery disease and by pharmacological treatment of diabetes (eFigure 2 in
Supplement 3
). No treatment heterogeneity was found according to baseline tertiles of blood lead or urine cadmium (eFigure 3 in
Supplement 3
).
Adverse Effects and Safety

Adverse events were captured from the time of randomization until 30 days after the final infusion. There were 81 serious adverse events (16.8%) in the active group and 79 (16.6%) in the placebo group (−0.2%; 95% CI, −4.9% to 4.6%; eTable 9 in
Supplement 3
). There were no unexpected serious adverse events.
Discussion

The primary finding of this study is that the clinical benefits of EDTA chelation found in the earlier TACT trial were not replicated. Thus, the findings herein do not support the clinical use of chelation to reduce CVD risk in US and Canadian participants with diabetes and a prior MI. The former TACT study, an NIH-sponsored randomized trial, conducted between 2002 and 2012, randomized 1708 participants with a prior MI to receive EDTA chelation or placebo and to receive high-dose oral vitamin and mineral therapy or placebo (factorial design). Biospecimens had not been collected in TACT. In 2013, a significant 18% relative reduction of the composite primary end point by EDTA was reported. Because of the association of clinical EDTA use with complementary and alternative medicine practices, the results of TACT were viewed by many in the allopathic medical community with considerable skepticism. The study results were published in 2013,
19
and the following year the American College of Cardiology and the American Heart Association assigned EDTA chelation as a class IIb recommendation.
20

The current study was designed specifically to replicate the earlier trial as closely as possible. The choice to restrict enrollment to participants with diabetes who already had experienced an MI was based primarily on the larger effect size for EDTA chelation in the diabetes subgroup, thus reducing the required sample size and cost of the replication trial. The current trial also explicitly proposed that clinical benefits of EDTA on CVD events would most likely be moderated by reductions in body stores of lead and cadmium.

The chelation infusion regimen in the current study was essentially the same as its predecessor. In the current trial’s EDTA group, blood lead level dropped by 61%. The prechelation urine cadmium levels, a marker of internal cadmium dose in the body, did not demonstrate a significant reduction in samples obtained prior to infusions 5, 20, and 40 compared with the baseline preinfusion.

Four possible explanations for the discordant findings between the 2 trials are worth noting briefly. First, differences in baseline risk levels can sometimes account for different trial outcomes. However, participants in the current trial had more advanced disease and higher CVD event rates than did those in the former trial, which usually leads to the expectation of a larger, not smaller, treatment effect size. Second, although the treatment of diabetes has undergone important changes between the 2 trials, including the use of sodium-glucose cotransporter-2 inhibitors
21
and glucagon-like peptide 1 agonists,
22
subgroup analyses did not provide any evidence that these newer treatments modified the effect of EDTA chelation relative to placebo infusion.

Third, National Health and Nutrition Examination Survey (NHANES) data suggest that participants in the current study may have had significantly lower baseline blood lead levels, the presumptive therapeutic target of EDTA, than participants in its predecessor study. A comparison of 634 participants in the 2003-2010 NHANES cycles with 503 in the 2015-2020 cycles showed a 35% decrease in median population blood lead levels from 17 μg/L to 11 μg/L.
23
Furthermore, lead in air pollution has decreased by 88% since 2010.
24
Even though the characteristics are similar between the NHANES subset and the TACT studies, the lack of blood samples from the 2013 study makes this hypothesis untestable.

Finally, the effect size for chelation in the initial study’s overall cohort was modest, and the larger treatment effect observed in the diabetes subgroup could have overestimated the actual treatment effect size. Bayesian sensitivity analyses using a skeptical or pessimistic prior (ie, ignoring prior clinical trial results) indicate that the current study results would be inconsistent with any primary end point benefit of clinically consequential size. Using optimistic priors based on the empirical results, however, suggests that EDTA may be clinically effective but with a substantially smaller effect size than was postulated for the current study. Because it was powered assuming a more optimistic 30% relative reduction in CVD events, the trial would be substantially underpowered to detect even the 18% reduction seen in its predecessor study.

Limitations

There are several limitations that warrant consideration. First, the primary analyses were restricted to a modified intention-to-treat population, for 41 randomized patients were excluded because they did not have at least 1 infusion after randomization. Sensitivity analyses including these patients are provided in the eTable 5 (
Supplement 3
), and there are no differences in overall results. Second, treatment adherence was imperfect. The full complement of 40 infusions was received by 68% of patients and at least 20 infusions by 78%. However, this is similar to adherence in the prior positive study. Third, there were 122 participants who were lost to follow-up or withdrew consent. Sensitivity analyses, again, did not show a plausible significant difference between groups (eTable7 in
Supplement 3
). Fourth, the therapeutic target of EDTA, population levels of blood lead decreased, between the initial study and the present study, possibly reducing the therapeutic efficacy of EDTA. Analyses covering both studies are covered in detail in the Results and Discussion sections.
Conclusions

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

Supplement 1.

Trial Protocol

jama-e2411463-s001.pdf
(559.7KB, pdf)

Supplement 2.

Statistical Analysis Plan

jama-e2411463-s002.pdf
(1.2MB, pdf)

Supplement 3.
eTable 1.
Reason for Exclusion among Screened Participants (Screening Population)

eTable 2.
Schedule of Evaluations

eTable 3.
Demographics and Baseline Clinical Characteristics for the ITT Population (Intention to Treat Population)

eTable 4.
Quest Labs Reference Ranges

eTable 5.
Sensitivity Analysis of the Primary Outcome for the ITT Population (Intention to Treat Population)

eTable 6.
Sensitivity Analysis of the Primary Outcome Excluding Events > 1 Year of the Latest Study Contact* (in the Primary Analysis Population)

eTable 7.
Sensitivity Analysis of the Primary Outcome with Imputation Scenarios for Consent Withdrawals and Patients Lost to Follow-up (in the Primary Analysis Population)

eTable 8.
Bayesian Sensitivity Analysis of the Primary Endpoint (in the Primary Analysis Population)

eFigure 1.
Bayesian Sensitivity Analysis of the Primary Endpoint with Prior/Posterior Density Plot for Optimistic Prior

eFigure 2.
Effects of EDTA versus Placebo Infusion on Primary Composite Outcome in Prespecified Subgroups (in the Primary Analysis Population)

eFigure 3.
Effects of EDTA versus Placebo Infusion on Primary Composite Outcome in Metal Tertiles Subgroups (in the Primary Analysis Population)

eTable 9.
Overview of Serious Adverse Non-Outcome Events (in the Primary Analysis Population

jama-e2411463-s003.pdf
(687.7KB, pdf)

Supplement 4.
Nonauthor Collaborators.
TACT2 Study Group

jama-e2411463-s004.pdf
(177.8KB, pdf)

Supplement 5.

Data Sharing Statement

jama-e2411463-s005.pdf
(14.6KB, pdf)

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Navas-Acien A, Santella RM, Joubert BR, et al. Baseline characteristics including blood and urine metal levels in the Trial to Assess Chelation Therapy 2 (TACT2). Am Heart J. 2024;273:72-82. doi: 10.1016/j.ahj.2024.04.005

[
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24.
Lead trends. Environmental Protection Agency . Accessed January 3, 2024.
https://www.epa.gov/air-trends/lead-trends

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jama-e2411463-s001.pdf
(559.7KB, pdf)

Supplement 2.

Statistical Analysis Plan

jama-e2411463-s002.pdf
(1.2MB, pdf)

Supplement 3.
eTable 1.
Reason for Exclusion among Screened Participants (Screening Population)

eTable 2.
Schedule of Evaluations

eTable 3.
Demographics and Baseline Clinical Characteristics for the ITT Population (Intention to Treat Population)

eTable 4.
Quest Labs Reference Ranges

eTable 5.
Sensitivity Analysis of the Primary Outcome for the ITT Population (Intention to Treat Population)

eTable 6.
Sensitivity Analysis of the Primary Outcome Excluding Events > 1 Year of the Latest Study Contact* (in the Primary Analysis Population)

eTable 7.
Sensitivity Analysis of the Primary Outcome with Imputation Scenarios for Consent Withdrawals and Patients Lost to Follow-up (in the Primary Analysis Population)

eTable 8.
Bayesian Sensitivity Analysis of the Primary Endpoint (in the Primary Analysis Population)

eFigure 1.
Bayesian Sensitivity Analysis of the Primary Endpoint with Prior/Posterior Density Plot for Optimistic Prior

eFigure 2.
Effects of EDTA versus Placebo Infusion on Primary Composite Outcome in Prespecified Subgroups (in the Primary Analysis Population)

eFigure 3.
Effects of EDTA versus Placebo Infusion on Primary Composite Outcome in Metal Tertiles Subgroups (in the Primary Analysis Population)

eTable 9.
Overview of Serious Adverse Non-Outcome Events (in the Primary Analysis Population

jama-e2411463-s003.pdf
(687.7KB, pdf)

Supplement 4.
Nonauthor Collaborators.
TACT2 Study Group

jama-e2411463-s004.pdf
(177.8KB, pdf)

Supplement 5.

Data Sharing Statement

jama-e2411463-s005.pdf
(14.6KB, pdf)

Articles from JAMA are provided here courtesy of
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</reference>

<statements>
1. EDTA chelation lowered blood lead but did not reduce major adverse cardiovascular events in TACT2 (hazard ratio 0.93, 95% CI 0.76–1.16)
2. TACT2 notes that worldwide analyses estimated more than 5.5 million cardiovascular deaths in 2019 attributable to low-to-moderate lead exposure, that cadmium is ubiquitous and atherogenic, and that an American Heart Association scientific statement recognized lead, cadmium, and arsenic as risk factors for atherosclerosis
3. The earlier TACT trial reported an 18% reduction in cardiovascular events with EDTA chelation in patients with prior myocardial infarction, and a 41% reduction in the diabetes subgroup; in 2014, the American College of Cardiology and American Heart Association assigned EDTA chelation a class IIb recommendation
4. It was a multicenter, double-masked, placebo-controlled 2 × 2 factorial trial in participants aged 50 years or older with diabetes and prior myocardial infarction, randomizing 1,000 participants to 40 weekly EDTA-based or placebo infusions and also randomizing high-dose oral multivitamins and minerals versus placebo, though the cited report addresses the chelation comparison
5. In the primary analysis population of 959 participants who received at least one infusion, the primary composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina occurred in 35.6% of the chelation group and 35.7% of the placebo group, with an adjusted hazard ratio of 0.93 (95% CI 0.76–1.16; P = .53)
6. Five-year cumulative incidence was 45.8% with chelation and 46.5% with placebo
7. Secondary cardiovascular death, myocardial infarction, or stroke showed no significant difference (hazard ratio 0.89, 95% CI 0.66–1.19), and all-cause mortality was similar (hazard ratio 0.96, 95% CI 0.71–1.30)
8. The trial nevertheless demonstrated biological target engagement: median blood lead fell from 9.03 μg/L at baseline to 3.46 μg/L at the 40th infusion, a 61% reduction, whereas placebo changed little
9. Urine cadmium levels did not show a clinically relevant sustained preinfusion reduction, although cadmium excretion transiently increased after infusion
10. Serious adverse events were similar between groups, and no unexpected serious adverse events occurred
11. The authors concluded that, despite effectively reducing blood lead, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease, diabetes, and prior myocardial infarction, and that the findings do not support clinical use of chelation for cardiovascular risk reduction in U.S. and Canadian participants with diabetes and prior myocardial infarction
12. TACT2 participants had more advanced disease and higher event rates, which would usually favor a larger treatment effect, yet the result was null
13. The authors note that population blood lead levels declined between the two trials, with NHANES median blood lead falling 35% from 17 to 11 μg/L and lead in air pollution decreasing 88% since 2010, potentially reducing the therapeutic target available for chelation
14. Bayesian sensitivity analyses using skeptical or pessimistic priors were inconsistent with clinically consequential benefit, whereas optimistic priors based on TACT suggested a possible smaller effect, with a posterior hazard ratio of 0.81 (95% credible interval 0.68–0.96) under the TACT diabetes-subgroup prior
15. The trial was designed assuming a 30% relative reduction and would have been underpowered to detect the 18% reduction seen in TACT
16. EDTA chelation is the clearest counterexample: it lowered blood lead effectively but did not reduce major adverse cardiovascular events in TACT2
17. TACT2 shows that target engagement does not guarantee clinical efficacy: lead lowering occurred without event reduction, possibly because population lead exposure had declined or because the prior effect size was overestimated
18. The supplied evidence extends to a 2025 intravenous iron meta-analysis and a 2024 TACT2 trial, but it does not provide 2026 guideline updates or completed trials of zinc modulation, copper lowering, hepcidin modulation, or dialysate magnesium with cardiovascular endpoints
</statements>

Begin the assessment now. Output only the JSON list, without any conversational text or explanations.