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 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.

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

Design Overview - Factorial Trial IV Chelation + ORAL high-dose vitamins IV Placebo chelation + ORAL placebo vitamins 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

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

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 

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/m2) 29.2 (26.5, 33.4) 29.9 (27.0, 33.8) 0.057 Female 17% 16% 0.809 Hispanic or non-Caucasian 8% 9% 0.574 Diabetes 38% 34% 0.207 Prior revascularization 83% 84% 0.879 Statin 74% 72% 0.558 Beta-blocker 70% 0.892 Aspirin 87% 79% 0.003 Aspirin, warfarin or clopidogrel 93% 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 infusions 40 (32, 40) 40 (30, 40) 0.554 Discontinued infusions 27% 31% 0.218 Completed 30 infusions 77% 75% 0.565 Completed 40 infusions 67% 65% 0.535 Discontinued vitamins 44% 47% 0.383 Continued vitamins for at least 1 year 78% 74% 0.224 Continued vitamins for at least 3 years 50% 48% 0.593 Consent withdrawal 12% 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 = 0.016 8.3%

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

Endpoints EDTA Chelation and High-Dose Vitamins (N=421) Placebo Infusions and Placebo Vitamins (N=437) Hazard Ratio (95% CI) P-value Primary Endpoint 26% 32% 0.74 (0.57, 0.95) 0.016 CVD, MI or stroke 9% 13% 0.66 (0.44, 0.99) 0.046 Death 10% 11% 0.87 (0.57, 1.30) 0.481 Cardiovascular death (CVD) 5% 6% 0.75 (0.41, 1.37) 0.383 MI 7% 0.71 (0.42, 1.21) 0.230 Stroke 1% 2% 0.44 (0.13, 1.42) 0.135 Coronary revascularization 14% 19% 0.67 (0.48, 0.94) 0.019 Hospitalization for angina 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 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 Cardiovasc Qual Outcomes. 2014

TACT Primary Endpoint in Diabetes Subgroup

TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins

TACT Primary Endpoint in Diabetes Subgroup Placebo Infusions / Placebo Vitamins Placebo Infusions / High-Dose 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 < 0.001

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