Clinical benefit of a disodium EDTA- based chelation therapy and high-dose oral multivitamins and...

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 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

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 mLPLACEBO INFUSION

normal saline, 1.2% dextrose, 500 mL

Chelation Components

TACT: High-Dose Oral Treatment

3 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 D3

Vitamin EVitamin KThiaminNiacin

VitaminB6

FolateVitamin B12

BiotinPanthothenic Acid

Calcium 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) 0.386

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% 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 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

Eve

nt

Rat

eTACT Primary Endpoint:

Factorial GroupsEDTA Chelation/High-dose

Vitamins vs. Placebo/Placebo

HR (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


Eve

nt

Rat

eTACT Secondary

Composite Endpoint

EDTA Chelation/High-dose Vitamins vs. Placebo

HR (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


Eve

nt

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


Eve

nt

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


Eve

nt

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


Eve

nt

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


Eve

nt

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

Clinical benefit of a disodium EDTA- based chelation therapy and high-dose oral multivitamins and...

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