1. 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.

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 % 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.

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
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

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
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

12. 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

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 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

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 , 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

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 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