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, FLFor 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 chelation3. Active oral vitamins + placebo IV chelation4. 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. 2012 Jan;163(1):7-12.

Calcium Iodine

MagnesiumZinc

SeleniumCopper

Manganese Chromium

MolybdenumPotassium

CholineBoron

InositolPABA

VanadiumCitrus Flavonoids

Vitamin AVitamin CVitamin D3

Vitamin EVitamin KThiaminNiacin

VitaminB6

FolateVitamin B12

BiotinPanthothenic 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 Characteristics1708 patients randomized

High Dose Vitamins(N=853)

Placebo (N=855)

Age (years) 65 (59, 72) 65 (60, 72)BMI (kg/m2) 29 (26, 33) 30 (27, 34)Female (%) 17 18

Hispanic or non-Caucasian (%) 9 9

Diabetes (%) 33 30

Prior revascularization (%) 83 83

Statin (%) 74 72Beta Blocker (%) 71 73Aspirin (%) 85 82Aspirin, clopidogrel, or warfarin (%) 92 90

LDL (mg/dL) 88 89

TACT Primary Endpoint Resultsfor EDTA Chelation (presented at AHA 2012)

EDTA: Placebo

HR (95% CI)0.82 (0.69, 0.99)

P = 0.035

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 = 0.212

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 Endpoint 230 (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 Infarction 58 (7%) 61 (7%) 0.95 (0.66, 1.36) 0.786

Stroke 8 (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 NInteraction

P-value HR 95% CI

All participants 1708 0.89 0.75, 1.07

Infusions 0.94EDTA 839 0.89 0.68, 1.15Placebo 869 0.90 0.7, 1.15

Gender 0.17Male 1409 0.84 0.69, 1.03Female 299 1.17 0.75, 1.83

Anterior MI    0.79  Yes 674 0.93 0.69, 1.26No 1034 0.88 0.7, 1.09

Diabetes 0.72Yes 538 0.84 0.62, 1.14No 1170 0.90 0.72, 1.12

Statins at baseline 0.01

Yes 1248 1.03 0.84, 1.27No 460 0.62 0.44, 0.87

CAM site 0.39Yes 1089 0.84 0.67, 1.05No 619 0.99 0.74, 1.33

4.01.00.25High-Dose

Vitamins BetterPlacebo

Better

2.00.5

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 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