Randomized Comparison of High-Dose Oral Vitamins versus Placebo in the Trial to Assess Chelation Therapy (TACT) Gervasio A. Lamas, MD, FACC Professor of Clinical Medicine Columbia University Division of Cardiology Mount Sinai Medical Center Miami Beach, FL For the TACT Investigators

Study Organization Funding agencies: NHLBI and NCCAM Clinical Coordinating Center: Mount Sinai Medical Center, Miami Beach FL Data Coordinating Center and EQOL Coordinating Center: Duke Clinical Research Institute Clinical Events Committee: Brigham and Women’s Hospital Central Pharmacy: Universal Arts, Miami FL Vitamins: Douglas Labs, Pittsburgh PA

Background  TACT tested whether EDTA chelation reduced a composite cardiovascular endpoint in post-MI patients.  Chelation practitioners use high doses of anti-oxidant vitamins and minerals in conjunction with intravenous chelation.  Uncontrolled use of oral vitamins and minerals therefore constituted a potential confounder.

Design Rationale To clarify the relative contributions of high- dose vitamins and IV chelation, TACT was designed as a 2 x 2 factorial trial, with patients randomized to 4 groups: 1.Active oral vitamins + active IV chelation 2.Placebo oral vitamins + active IV chelation 3.Active oral vitamins + placebo IV chelation 4.Placebo oral vitamins + placebo IV chelation

TACT: High-Dose Oral Treatment Double-blind active or placebo high dose vitamins were shipped from a central pharmacy to sites. 3 caplets twice a day for the duration of the study. Lamas GA, Goertz C, Boineau R, et. al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J Jan;163(1):7-12. Calcium Iodine Magnesium Zinc Selenium Copper Manganese Chromium Molybdenum Potassium Choline Boron Inositol PABA 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

Eligibility  Age 50 or older  MI > 6 weeks 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  No cigarette smoking within 3 months  Signed informed consent

Primary Endpoint  Primary composite endpoint: time to first occurrence of either death, MI, stroke, coronary revascularization, or hospitalization for angina

Statistical Plan  Designed to have 85% power to detect a 25% difference  Treatment comparisons as randomized (intent to treat)  Two-sided statistical testing  Log-rank test using time to first event  Prespecified analysis of factorial groups

Baseline Characteristics 1708 patients randomized High Dose Vitamins (N=853) Placebo (N=855) Age (years)65 (59, 72)65 (60, 72) BMI (kg/m 2 )29 (26, 33)30 (27, 34) Female (%)1718 Hispanic or non-Caucasian (%) 99 Diabetes (%)3330 Prior revascularization (%)83 Statin (%)7472 Beta Blocker (%)7173 Aspirin (%)8582 Aspirin, clopidogrel, or warfarin (%) 9290 LDL (mg/dL)8889

TACT Primary Endpoint Results for EDTA Chelation (presented at AHA 2012) EDTA: Placebo HR (95% CI) 0.82 (0.69, 0.99) P = Death, MI, stroke, coronary revascularization, hospitalization for angina

TACT Vitamin Primary Endpoint Results Vitamins: Placebo HR (95% CI) 0.89 (0.75, 1.07) P = Death, MI, stroke, coronary revascularization, hospitalization for angina 34% 37% Median follow-up 55 months

Components of the Primary Endpoint High Dose Vitamins (N= 853) Placebo (N= 855) Hazard Ratio (95% CI) P Value Primary Endpoint230 (27%)253 (30%)0.89 (0.75, 1.07)0.212 Death 87 (10%) 93 (11%)0.93 (0.69, 1.24)0.614 Myocardial Infarction58 (7%) 61 (7%)0.95 (0.66, 1.36)0.786 Stroke8 (1%) 15 (2%)0.53 (0.22, 1.25)0.139 Coronary revascularization 132 (15%) 155 (18%)0.84 (0.66, 1.05)0.131 Hospitalization for angina 12 (1%) 19 (2%)0.72 (0.35, 1.47)0.359

Subgroup Results for Vitamin Analyses Participant Group N Interaction P-valueHR95% CI All participants , 1.07 Infusions0.94 EDTA , 1.15 Placebo , 1.15 Gender0.17 Male , 1.03 Female , 1.83 Anterior MI 0.79 Yes , 1.26 No , 1.09 Diabetes0.72 Yes , 1.14 No , 1.12 Statins at baseline0.01 Yes , 1.27 No , 0.87 CAM site0.39 Yes , 1.05 No , High-Dose Vitamins Better Placebo Better

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

Adherence 75.6% took study vitamins for at least 1 year. – The most common reason for discontinuation was patient refusal (75%) – Median duration of treatment: 33.4 months. – No difference in discontinuation rate in active vs placebo vitamins.

Limitations Compliance with high-dose vitamin regimen was challenging, leading to some non-adherence. High consent withdrawal rate (17%). The therapeutic mechanisms by which high-dose vitamins and chelation might provide benefits are unclear.

Summary  High dose oral vitamins reduced the composite outcome by 11%, which was not statistically significant.  When combined with EDTA chelation, the small vitamin benefit was additive, and the combined effect was statistically significant.

Caveats The results of this study do not support the use of high- dose vitamin and mineral therapy as an adjunct to optimal evidence-based medical therapy in patients with prior myocardial infarction. These findings should stimulate further research, but are not, by themselves, sufficient to recommend the routine use of chelation therapy and high-dose vitamins in post- MI patients.

Thank you