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Clinical Benefit of EDTA Chelation Therapy in Patients with Diabetes in the Trial to Assess Chelation Therapy (TACT).

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slide1

Clinical Benefit of EDTA Chelation Therapy in Patients with Diabetes in the Trial to Assess Chelation Therapy (TACT)

Esteban Escolar, Gervasio A. Lamas, Daniel Mark, Pamela Ouyang, Allan Magaziner, Robin Boineau, Ralph Miranda, Christine Goertz, Yves Rosenberg, Richard Nahin, Richard Nahas, Eldrin Lewis, Lauren Lindblad, Kerry L Lee

For the TACT Investigators

No disclosures to report

The National Center for Complementary and Alternative Medicine (U01AT001156) and the National Heart, Lung and Blood Institute (U01HL092607) provided sole support for this study.

background
Background
  • Disodium ethylene diamine tetra acetic acid (EDTA) binds metal cations and permits renal excretion
  • Since 1956, EDTA chelation has been used to treat atherosclerotic disease without evidence of benefit.
  • In 2001, NCCAM and NHLBI released an RFA for a definitive trial of EDTA chelation
background1
Background
  • TACT showed a statistically significant reduction of a combined cardiovascular endpoint (HR 0.82 [95% CI, 0.69-0.99]; p = 0.035) with an EDTA-based infusion regimen in patients with prior MI
  • There was an interaction between chelation infusion and self-reported diabetes
  • The present analyses provide greater detail on the effect of chelation therapy in patients with diabetes

Lamas GA, Goertz C, Boineau R , et. al. JAMA. 2013;309(12):1241-1250

design overview
Design Overview

40 infusions at least 3 hours each; 30 weekly infusions followed by10 maintenance infusions 2-8 weeks apart.

Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012 Jan;163(1):7-12. 

infusion components
Infusion components

Chelation Infusion

  • disodium EDTA, 3 grams (adjusted by GFR)
  • ascorbic acid, 7 grams
  • magnesium chloride, 2 grams
  • potassium chloride, 2 mEq
  • sodium bicarbonate, 840 mg
  • pantothenic acid, thiamine, pyridoxine
  • procaine, 100 mg
  • unfractionated heparin, 2500 U
  • sterile water to 500 mL

Placebo Infusion

  • Normal Saline
  • 1.2% dextrose, 500 mL

Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012 Jan;163(1):7-12. 

inclusion criteria
Inclusion Criteria
  • Age 50 or older
  • MI > 6 months prior
  • Creatinine < 2.0 mg/dL
  • No coronary or carotid revascularization within 6 months
  • No active heart failure or heart failure hospitalization within 6 months
  • Able to tolerate 500cc infusions weekly
  • No cigarette smoking within 3 months
  • Signed informed consent
end points
End points
  • Primary endpoint:
  • Time to first occurrence of either
    • death from any cause,
    • reinfarction,
    • stroke,
    • coronary revascularization, or
    • hospitalization for angina
  • Secondary endpoint:
  • Time to first occurrence of either
    • cardiovascular death,
    • reinfarction, or
    • stroke
dm definition
DM definition
  • Self-reported diabetes
  • Treated for diabetes
  • Fasting blood glucose ≥126 mg/dLprior to enrollment

These criteria expanded the population with diabetes from 538 to 633 patients, or 37% of the study subjects

statistical analysis
Statistical Analysis
  • Log-rank test – Comparisons between arms for clinical events.
  • Intention to treat analysis
  • Treatment comparisons:
  • Cumulative event rates - Kaplan-Meier method
  • RR expressed as HR with 95% CI (Cox model)and nominal p values are reported
  • Bonferroniadjusted confidence intervals and p-values, adjusted for 9 different subgroup factors
slide10

Baselinecharacteristicsofpatients with or without Diabetes

For all continuous variables [median (25th, 75th)].

slide11

Baseline characteristics of patients with

Diabetes by infusion arm

For all continuous variables [median (25th, 75th)]. p >0.05 for all comparisons

primary endpoint by infusion arm diabetes
Primary Endpoint by infusion arm Diabetes

Placebo Infusions

EDTA Chelation vs. Placebo

HR (95% CI): 0.59 (0.44, 0.79); P = 0.0002

Bonferroni Adjusted: (0.39, 0.88); P = 0.002

EDTA Chelation

RR = 41%

NNT = 6.5 over 5 years CI (4.4, 12.7)

Number at Risk:

EDTA Chelation 322 286 262 243 217 198 187 177 157 126 74

Placebo 311 270 235 214 187 168 155 134 116 94 63

primary endpoint by infusion arm
Primary Endpoint by infusion arm

Diabetes

No Diabetes

EDTA Chelation vs. Placebo

HR (95% CI): 0.59 (0.44, 0.79); P = 0.0002

Adjusted: (0.39, 0.88); P = 0.002

EDTA Chelation vs. Placebo

HR (95% CI): 1.02 (0.81, 1.28); P = 0.8768

Placebo Infusions

EDTA Chelation

Number at Risk:

EDTA Chelation 322 286 262 243 217 198 187 177 157 126 74

517 474 441 407 371 339 324 299 270 232 155

Placebo 311 270 235 214 187 168 155 134 116 94 63

558 506 466 424 379 347 320 295 268 228 142

secondary endpoint by infusion arm diabetes
Secondary Endpoint by infusion arm Diabetes

EDTA Chelation vs. Placebo

HR (95% CI): 0.60 (0.39, 0.91); P = 0.0170

Bonferroni Adjusted: (0.32, 1.09); P = 0.153

Number at Risk:

EDTA Chelation 322 293 275 259 236 219 210 201 182 149 90

Placebo 311 276 252 231 206 190 180 161 139 117 79

death by infusion arm diabetes
Death by infusion arm - Diabetes

EDTA Chelation vs. Placebo

HR (95% CI): 0.57 (0.36, 0.88); P = 0.0111

Bonferroni Adjusted: (0.30, 1.06); P = 0.099

Number at Risk:

EDTA Chelation 322 303 283 267 251 230 222 211 193 160 101

Placebo 311 293 275 250 227 205 195 174 151 128 83

limitations
Limitations
  • Although this subgroup analysis was prespecified, subgroup findings, regardless of how robust they appear, must be considered hypothesis-generating
  • A moderate number of patients withdrew consent, limiting somewhat the events that could be accrued and attributed during follow-up
conclusions
Conclusions
  • Post-MI diabetic patients age 50 or older on evidence-based medications demonstrated a marked reduction in cardiovascular events with EDTA-based chelationtherapy
  • These findings support the initiation of clinical trials in patients with diabetes and vascular disease to replicate these findings, and define the mechanisms of benefit
  • They do not, as yet, constitute sufficient evidence to indicate routine use of chelation therapy for post-MI diabetic patients
slide18

This article is now available online in

Circulation: Cardiovascular Quality & Outcomes

http://circoutcomes.ahajournals.org/content/early/2013/11/19/CIRCOUTCOMES.113.000663