background

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, FAHAColumbia University Division of Cardiology at Mount Sinai Medical Center, Miami Beach FL

Professor of MedicineColumbia 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.

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 placebo6 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 Treatment3 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

MagnesiumZinc

SeleniumCopper

Manganese Chromium

MolybdenumPotassium

CholineInositolPABABoron

VanadiumCitrus Flavonoids

Vitamin AVitamin CVitamin D3Vitamin EVitamin KThiaminNiacin

VitaminB6Folate

Vitamin B12Biotin

Panthothenic AcidCalcium

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 CharacteristicsEDTA

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) 0.386BMI (kg/m2) 29.2 (26.5, 33.4) 29.9 (27.0, 33.8) 0.057Female 17% 16% 0.809Hispanic or non-Caucasian 8% 9% 0.574Diabetes 38% 34% 0.207Prior revascularization 83% 84% 0.879Statin 74% 72% 0.558Beta-blocker 70% 70% 0.892Aspirin 87% 79% 0.003Aspirin, warfarin or clopidogrel 93% 89% 0.110LDL (mg/dL) 88.0 (66.5,

113.5)93.0 (71.0,

122.0)0.028

Treatment AdherencePatient 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

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5

Placebo Infusions/Placebo VitaminsPlacebo Infusions/High-Dose Vi-taminsEDTA Chelation/Placebo VitaminsEDTA Chelation/High-Dose Vitamins

Months since randomization

Even

t Rat

eTACT Primary Endpoint:

Factorial GroupsEDTA Chelation/High-dose

Vitamins vs. Placebo/PlaceboHR (95% CI): 0.74 (0.57, 0.95)

P = 0.016 8.3%

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

eTACT Secondary

Composite Endpoint

EDTA Chelation/High-dose Vitamins vs. PlaceboHR (95% CI): 0.66 (0.44, 0.99); P = 0.046

Placebo Infusions / Placebo Vitamins

EDTA Chelation / High-Dose Vitamins

EndpointsEDTA

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 5% 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 1% 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

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

eTACT Primary Endpoint in

Diabetes Subgroup

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e


TACT Primary Endpoint in Diabetes Subgroup

0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e

Placebo Infusions / High-Dose Vitamins



0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e



EDTA Chelation / Placebo Vitamins


0 6 12 18 24 30 36 42 48 54 600

0.1

0.2

0.3

0.4

0.5


Even

t Rat

e



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

background

Documents

highdose oral vitamins

highdose oral multivitamins

double placebo armexamine

minerals vs placebo

goertz c

boineau r

factorial cells

double active arm vs