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For the TACT Investigators

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1 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 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.

2 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

3 Background TACT showed a statistically significant reduction of a combined cardiovascular endpoint (HR 0.82 [95% CI, ]; 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):

4 Design Overview Chelation + high-dose vitamins
Placebo chelation + high-dose vitamins Chelation + 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 Jan;163(1):7-12. 

5 Infusion components 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 Placebo Infusion Normal Saline 1.2% dextrose, 500 mL Lamas GA, Goertz C, Boineau R, et. al. Am Heart J Jan;163(1):7-12. 

6 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

7 End points Primary endpoint: Time to first occurrence of either
death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina Secondary endpoint: cardiovascular death, reinfarction, or stroke

8 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 Fix a bit original and revised. Change before analysis was completed

9 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

10 Baseline characteristics of patients with or without Diabetes
No Diabetes (N=1075) P-value Age 65(59,71) 65(58,72) 0.784 Female (%) 19 17 0.280 BMI 31(28,36) 28(25,32) <0.001 CHF (%) 23 15 PVD (%) 22 12 HTN (%) 78 63 Hypercholesterolemia (%) 85 80 0.013 CABG (%) 49 43 0.008 PCI (%) 56 61 0.040 Statin (%) 76 72 0.063 ACE or ARB (%) 73 58 ASA/clopidogrel/warfarin 92 91 0.202 Fasting Glucose (mg/dL) 131(109,162) 97 (90,105) For all continuous variables [median (25th, 75th)].

11 Baseline characteristics of patients with Diabetes by infusion arm
Chelation (N=322) Placebo (N=311) Age 65 (60,71) 66 (58,71) Female (%) 17 21 BMI 31(28,36) 32(28,36) Anterior MI (%) 40 36 HTN (%) 78 Hypercholesterolemia (%) 86 84 PCI or CABG (%) 85 Statin (%) 77 75 ACE or ARB (%) 73 ASA/clopidogrel/warfarin (%) 93 92 LDL (mg/dL) 81(63,105) 85(63,115) Fasting Glucose(mg/dL) 129 (107,160) 134(109,165) For all continuous variables [median (25th, 75th)] p >0.05 for all comparisons

12 Primary Endpoint by infusion arm Diabetes
Placebo Infusions Placebo EDTA Chelation vs. Placebo HR (95% CI): 0.59 (0.44, 0.79); P = Bonferroni Adjusted: (0.39, 0.88); P = 0.002 EDTA Chelation EDTA Chelation RR = 41% NNT = 6.5 over 5 years CI (4.4, 12.7) Number at Risk:

13 Primary Endpoint by infusion arm
Diabetes No Diabetes Placebo Placebo Infusions EDTA Chelation vs. Placebo HR (95% CI): 1.02 (0.81, 1.28); P = HR (95% CI): 0.59 (0.44, 0.79); P = Adjusted: (0.39, 0.88); P = 0.002 EDTA Chelation EDTA Chelation Number at Risk:

14 Secondary Endpoint by infusion arm Diabetes
EDTA Chelation vs. Placebo HR (95% CI): 0.60 (0.39, 0.91); P = Bonferroni Adjusted: (0.32, 1.09); P = 0.153 Placebo EDTA Chelation Number at Risk:

15 Death by infusion arm - Diabetes
EDTA Chelation vs. Placebo HR (95% CI): 0.57 (0.36, 0.88); P = Bonferroni Adjusted: (0.30, 1.06); P = 0.099 Placebo EDTA Chelation Number at Risk:

16 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

17 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

18 This article is now available online in
Circulation: Cardiovascular Quality & Outcomes

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