For the TACT Investigators

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

The National Center for Complementary and Alternative Medicine (U01AT001156) and the National Heart, Lung and Blood Institute

(U01HL092607) provided sole support for this study.

No disclosures to report

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

• 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

Background

Design OverviewChelation + high-dose

vitaminsPlacebo chelation + high-

dose vitaminsChelation + placebo

vitamins Placebo chelation +

placebo vitamins

40 infusions at least 3 hours each; 30 weekly infusions followed by 10 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

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

Chelation Infusion

Placebo 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

• Normal Saline• 1.2% dextrose, 500 mL

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 pointsPrimary 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• Self-reported diabetes • Treated for diabetes• Fasting blood glucose ≥126 mg/dL prior to

enrollment

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

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• Bonferroni adjusted confidence intervals and p-

values, adjusted for 9 different subgroup factors

Diabetes(N=633)

No Diabetes(N=1075) P-value

Age 65(59,71) 65(58,72) 0.784Female (%) 19 17 0.280BMI 31(28,36) 28(25,32) <0.001CHF (%) 23 15 <0.001PVD (%) 22 12 <0.001HTN (%) 78 63 <0.001Hypercholesterolemia (%) 85 80 0.013CABG (%) 49 43 0.008PCI (%) 56 61 0.040Statin (%) 76 72 0.063ACE or ARB (%) 73 58 <0.001ASA/clopidogrel/warfarin 92 91 0.202Fasting Glucose (mg/dL) 131(109,162) 97 (90,105) <0.001

Baseline characteristics of patients with or without Diabetes

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

Chelation(N=322)

Placebo(N=311)

Age 65 (60,71) 66 (58,71)Female (%) 17 21BMI 31(28,36) 32(28,36)Anterior MI (%) 40 36HTN (%) 78 78Hypercholesterolemia (%) 86 84PCI or CABG (%) 85 78Statin (%) 77 75ACE or ARB (%) 73 73ASA/clopidogrel/warfarin (%) 93 92LDL (mg/dL) 81(63,105) 85(63,115)Fasting Glucose(mg/dL) 129

(107,160)134(109,165

)

Baseline characteristics of patients with Diabetes by infusion arm

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

Placebo Infusions

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

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5

Months since randomization

Even

t Ra

te

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

EDTA Chelation

EDTA Chelation vs. PlaceboHR (95% CI): 0.59 (0.44, 0.79); P = 0.0002Bonferroni Adjusted: (0.39, 0.88); P = 0.002

Number at Risk:

Primary Endpoint by infusion arm Diabetes

RR = 41%NNT = 6.5 over 5 years CI (4.4, 12.7)

Placebo 311 270 235 214 187 168 155 134 116 94 63 558 506 466 424 379 347 320 295 268 228 142

Placebo Infusions

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e

Number at Risk:

0 6 12 18 24 30 36 42 48 54 60


No Diabetes

EDTA Chelation

EDTA Chelation322 286 262 243 217 198 187 177 157 126 74 517 474 441 407 371 339 324 299 270 232 155

DiabetesEDTA Chelation vs. PlaceboHR (95% CI): 1.02 (0.81, 1.28); P = 0.8768

EDTA Chelation vs. PlaceboHR (95% CI): 0.59 (0.44, 0.79); P = 0.0002Adjusted: (0.39, 0.88); P = 0.002

Primary Endpoint by infusion arm

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e


EDTA Chelation 322 293 275 259 236 219 210 201 182 149 90Placebo 311 276 252 231 206 190 180 161 139 117 79

Number at Risk:

Secondary Endpoint by infusion arm Diabetes

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e


Number at Risk:

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

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

Death by infusion arm - Diabetes

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

• Post-MI diabetic patients age 50 or older on evidence-based medications demonstrated a marked reduction in cardiovascular events with EDTA-based chelation therapy

• 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

This article is now available online inCirculation: Cardiovascular Quality & Outcomes

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

For the TACT Investigators

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