Clinical benefit of a disodium EDTA- based chelation therapy and high-dose oral multivitamins and multiminerals in TACT- comparison of factorial groups Gervasio Lamas MD, FAHA Columbia University Division of Cardiology at Mount Sinai Medical Center, Miami Beach FL Professor of Medicine Columbia 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.

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

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 % CI (0.75,1.07), p=0.212)** * Lamas GA, Goertz C, Boineau R, et. al. JAMA. 2013;309(12): ** Lamas G, Boineau R, Goertz C, et al. Ann Intern Med. 2013;159(12): in Press.

  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 Purpose

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 IV Chelation + ORAL high-dose vitamins IV Placebo chelation + ORAL high-dose vitamins IV Chelation + ORAL placebo vitamins IV Placebo chelation + ORAL placebo vitamins

  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 Chelation Components

TACT: High-Dose Oral Treatment 3 caplets twice a day for the duration of the study Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012;163(1):7-12 Magnesium Zinc Selenium Copper Manganese Chromium Molybdenum Potassium Choline Inositol PABA Boron Vanadium Citrus Flavonoids Vitamin A Vitamin C Vitamin D 3 Vitamin E Vitamin K Thiamin Niacin VitaminB 6 Folate Vitamin B 12 Biotin Panthothenic Acid Calcium Iodine

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

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

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

Baseline Characteristics EDTA Chelation and High-Dose Vitamins (N=421) Placebo Infusions and Placebo Vitamins (N=437) P-value Age (years)64.9 (58.8, 71.4)65.5 (59.2, 71.9)0.386 BMI (kg/m 2 )29.2 (26.5, 33.4)29.9 (27.0, 33.8)0.057 Female17%16%0.809 Hispanic or non-Caucasian8%9%0.574 Diabetes38%34%0.207 Prior revascularization83%84%0.879 Statin74%72%0.558 Beta-blocker70% Aspirin87%79%0.003 Aspirin, warfarin or clopidogrel93%89%0.110 LDL (mg/dL)88.0 (66.5, 113.5)93.0 (71.0, 122.0)0.028

Treatment Adherence Patient Status EDTA Chelation and High-Dose Vitamins (N=421) Placebo Infusions and Placebo Vitamins (N=437) P-value Number of infusions40 (32, 40)40 (30, 40)0.554 Discontinued infusions27%31%0.218 Completed 30 infusions77%75%0.565 Completed 40 infusions67%65%0.535 Discontinued vitamins44%47%0.383 Continued vitamins for at least 1 year78%74%0.224 Continued vitamins for at least 3 years50%48%0.593 Consent withdrawal12%19%0.004

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

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

Endpoints EDTA Chelation and High-Dose Vitamins (N=421) Placebo Infusions and Placebo Vitamins (N=437) Hazard Ratio (95% CI)P-value Primary Endpoint26%32%0.74 (0.57, 0.95)0.016 CVD, MI or stroke9%13%0.66 (0.44, 0.99)0.046 Death10%11%0.87 (0.57, 1.30)0.481 Cardiovascular death (CVD)5%6%0.75 (0.41, 1.37)0.383 MI5%7%0.71 (0.42, 1.21)0.230 Stroke1%2%0.44 (0.13, 1.42)0.135 Coronary revascularization14%19%0.67 (0.48, 0.94)0.019 Hospitalization for angina1%3%0.49 (0.18, 1.31)0.119

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 , 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 Cardiovasc Qual Outcomes. 2014

TACT Primary Endpoint in Diabetes Subgroup

Placebo Infusions / Placebo Vitamins TACT Primary Endpoint in Diabetes Subgroup

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

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

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

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

Conclusions   Analysis of the 2 active arm vs the 2 placebo arm in TACT suggests greater benefit when chelation is accompanied by 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