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  1. Clinical benefit of a disodium EDTA-based chelation therapy and high-dose oral multivitamins and multiminerals in TACT-comparison of factorial groups Gervasio LamasMD, FAHAColumbia University Division of Cardiology at Mount Sinai Medical Center, Miami Beach FLProfessor of MedicineColumbia University Medical Center 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 • In 2001, NCCAM and NHLBI released an RFA for a definitive trial of EDTA chelation • The Trial to Assess Chelation Therapy was a 2 x 2 factorial trial that randomized patients to IV EDTA chelation or placebo, and high-dose oral vitamins and minerals or placebo

  3. Background • Comparison of EDTA chelation vs placebo showed a 18% reduction in the combined primary cardiovascular endpoint: HR 0.82; 95%CI (0.69,0.99), p=0.035)* • Comparison of oral high-dose vitamins and minerals vs placebo showed an 11% reduction in the combined primary cardiovascular endpoint: HR 0.89 95% CI (0.75,1.07), p=0.212)** * Lamas GA, Goertz C, Boineau R , et. al. JAMA. 2013;309(12):1241-1250 ** Lamas G, Boineau R, Goertz C, et al. Ann Intern Med. 2013;159(12): in Press.

  4. Purpose • The purpose of the present analyses is to examine outcomes in all four factorial groups, with emphasis on the double active arm vs the double placebo arm • Examine the factorial cells in patients with diabetes

  5. Design Overview - Factorial Trial 40 infusions, double blind active or placebo 6 vitamin caplets daily – double blind active or placebo Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012;163(1):7-12

  6. Chelation Components • disodium EDTA, 3 grams, adjusted downward based on eGFR • 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

  7. TACT: High-Dose Oral Treatment 3 caplets twice a day for the duration of the study Vitamin A Vitamin C Vitamin D3 Vitamin E Vitamin K Thiamin Niacin VitaminB6 Folate Vitamin B12 Biotin Panthothenic Acid Calcium Iodine Magnesium Zinc Selenium Copper Manganese Chromium Molybdenum Potassium Choline Inositol PABA Boron Vanadium Citrus Flavonoids Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012;163(1):7-12

  8. Eligibility • 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

  9. Endpoints & Power • Primary composite endpoint: death, MI, stroke, coronary revascularization, hospitalization for angina • Study designed with 85% power for detecting a 25% difference • Secondary endpoint: CV death, MI, stroke • Individual components of the primary and secondary endpoints

  10. Data Analysis • Treatment comparisons as randomized (intent to treat) • Two-sided statistical testing • Log-rank test using time to first event • The present analyses focus on the 2 active arm vs the 2 placebo arm. Groups receiving only 1 intervention are shown for comparison purposes

  11. Baseline Characteristics

  12. Treatment Adherence

  13. TACT Primary Endpoint: Factorial Groups EDTA Chelation/High-dose Vitamins vs. Placebo/Placebo HR (95% CI): 0.74 (0.57, 0.95) P = 0.016 8.3%

  14. TACT Secondary Composite Endpoint Placebo Infusions / Placebo Vitamins EDTA Chelation / High-Dose Vitamins EDTA Chelation/High-dose Vitamins vs. Placebo HR (95% CI): 0.66 (0.44, 0.99); P = 0.046

  15. Endpoints

  16. Analysis of Patients with Diabetes • Yesterday we presented and published that TACT patients with pre-specified diabetes have a significant reduction of the primary endpoint with EDTA chelation (HR 0.59; 95% CI 0.44-0.79, p<0.001)* • We analyzed whether the modest additive effect of oral vitamins was also evident in this population * Escolar E, Lamas GA Mark DB, et al. Circ CardiovascQual Outcomes. 2014

  17. TACT Primary Endpoint in Diabetes Subgroup

  18. TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins

  19. TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins Placebo Infusions / High-Dose Vitamins

  20. TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins Placebo Infusions / High-Dose Vitamins EDTA Chelation / Placebo Vitamins

  21. TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins Placebo Infusions / High-Dose Vitamins EDTA Chelation / Placebo Vitamins EDTA Chelation / High-Dose Vitamins

  22. TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins EDTA Chelation / High-Dose Vitamins EDTA Chelation/High-dose Vitamins vs. Placebo HR (95% CI): 0.49 (0.33, 0.75) P <0.001

  23. Study Limitations • The TACT regimen is difficult, with 40 IV infusions and 6 large caplets daily, leading to non-adherence for some patients • A larger than expected number of patients withdrew consent • Overall, vitamin therapy produced a non-significant 11% reduction in events.  However, this modest reduction was additive to the 18% reduction observed with chelation, leading to a 26% reduction with active + active compared with placebo + placebo

  24. Conclusions • Analysis of the 2 active arm vs the 2 placebo arm in TACT suggests greater benefit when chelation is accompaniedby high-dose oral vitamins • This benefit of chelation + vitamins compared to placebo + placebo is statistically significant and of a magnitude sufficient to be clinically important, with a number needed to treat of 12 to prevent 1 primary event over 5 years. • The benefit of vitamin therapy added to EDTA chelation is magnified in the subgroup of patients with diabetes, with a number needed to treat of 5.5 to prevent 1 primary event over 5 years

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