2/10/2014. chemwiki.ucdavis.edu

Transcription

1 Chelation Therapy in CAD: The Trial to Assess Chelation Therapy (TACT) Gervasio A. Lamas MD Professor of Medicine Columbia University Medical Center Chairman of Medicine Mount Sinai Medical Center Miami Beach FL The National Center for Complementary and Alternative Medicine (U1AT1156) and the National Heart, Lung and Blood Institute (U1HL9267) provided sole support for this study. EDTA chemwiki.ucdavis.edu What Does EDTA Chelate? Baseline Urinary Excretion Before EDTA Infusion ng/mg urinary creatine Increase in Urinary Excretion After EDTA Infusion ng/mg urinary creatine Percent Increase of Baseline Excretion Element Manganese % Zinc % Iron % Cobalt % Calcium % Lead % Magnesium % Cadmium % Nickel % Aluminum % Sodium % Selenium % Lithium % Copper % Phosphorous % Arsenic % Chromium % Potassium % Molybdenum % Cranton EM, Liu ZX,Smith IM. Urinary Trace and Toxic Elements and Minerals in Untimed Urine Specimens. In Textbook on EDTA Chelation Therapy, 2 nd Ed. 21 Hampton Roads 1

2 Metals with evidence in support of adverse cardiovascular effects Periodic Table of the Elements Evidence for harm at low-moderate levels is increasing Courtesy of Ana Navas-Acien 213 EDTA Chelation and Alternative Medicine (58 year history) Clarke 1956 reported improvement of angina By early 197s, mainstream medical interest in chelation had faded 1973 American College for Advancement in Medicine (ACAM) founded, in part to promote use of chelation rx ACAM physicians modified and standardized rx, added heparin, B vitamins, megadose vitamin C, and minerals All conventional medical societies have condemned chelation as dangerous and ineffective. Patients continue to seek out chelation. Lewin MR, Texas Heart Inst J, 1997 Mechanisms Reduced environmentally-acquired acquired xenobiotic metal toxicity o Extensive epidemiological evidence of association with CV disease o Oxidant stressors o Involved in formation of glycation end- products in diabetes o Involved in LDL oxidation Improved endothelial function o IV vitamin C in infusion 2

3 In July 21, the cardiology community knew Alternative medicine was bunk Chelation practitioners were quacks Chelation was quackery Oral high-dose multi-vitamins had nothing to offer cardiology A chelation trial should never be funded In August 212 we unblinded TACT An Improbable Event Had Occurred Taleb, Nassim Nicholas (21) [27], TACT timeline RFA for efficacy trial released by NCCAM & NHLBI 4/3/1 TACT funded as a cooperative agreement 8/15/2 IND obtained 4/23/3 First patient randomized 9/1/3 Patient 178 enrolled 1/4/1 Last patient follow-up 1/31/ enrolling sites (including Mayo Rochester) 3

4 Design Overview - Factorial Trial IV Chelation + ORAL high-dose vitamins IV chelation + ORAL high-dose vitamins IV Chelation + ORAL placebo vitamins IV chelation + ORAL placebo vitamins Double-blind active or placebo infusions were shipped from a central pharmacy to sites. 4 infusions at least 3 hours each; 3 weekly infusions followed by 1 maintenance infusions 2-8 weeks apart. Lamas GA, Goertz C, Boineau R, et. al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 212 Jan;163(1):7-12. CHELATION INFUSION disodium EDTA, 3 grams, adjusted downward based on egfr ascorbic acid, 7 grams magnesium chloride, 2 grams potassium chloride, 2 meq sodium bicarbonate, 84 mg pantothenic acid, thiamine, pyridoxine procaine, 1 mg unfractionated heparin, 25 U sterile water to 5 ml PLACEBO INFUSION normal saline, 1.2% dextrose, 5 ml Age 5 or older MI > 6 months prior Creatinine <2. mg/dl Eligibility No coronary or carotid revascularization within 6 months No active heart failure or heart failure hospitalization within 6 months Able to tolerate 5cc infusions weekly No cigarette smoking within 3 months Signed informed consent 4

5 Primary Endpoint & Sample Size Primary composite endpoint: death, MI, stroke, coronary revascularization, hospitalization for angina 17 patents with a median followup of about 5 years gave us 85% power for detecting a 25% difference Data Analysis Treatment comparisons as randomized (intent to treat) Two sided statistical testing Log-rank test using time to first event Baseline Characteristics 178 patients randomized EDTA Chelation (N=839) (N=869) Age (years) 65 (59, 72) 66 (59, 72) BMI (kg/m 2 ) 3 (27, 34) 3 (27, 34) Female (%) Hispanic or non-caucasian (%) 9 1 Diabetes (%) Prior revascularization (%) Statin (%) Beta Blocker (%) Aspirin (%) Aspirin, clopidogrel, or warfarin (%) 92 9 LDL (mg/dl)

6 Compliance Total 55,222 infusions 65% completed all 4 infusions; 76% completed at least 3 17% withdrew consent o Of these, 18% had an endpoint event before withdrawing consent o All had vital status assessed using the national death index TACT Primary Endpoint Results.38 Death, MI, stroke, coronary revascularization, hospitalization for angina Number at risk: TACT Primary Endpoint Results EDTA: HR (95% CI).82 (.69,.99) P =.35 EDTA Chelation Death, MI, stroke, coronary revascularization, hospitalization for angina Number at risk: EDTA chelation

7 Components of the Primary Endpoint EDTA Chelation (N= 839) (N= 869) Hazard Ratio (95% CI) P Value Primary Endpoint 222 (26.5%) 261 (3.%).82 (.69,.99).35 Death 87 (1%) 93 (1.7%).93 (.7, 1.25).642 Myocardial Infarction 52 (6.2%) 67 (7.7%).77 (4, 1.11) 68 Stroke 1 (1.2%) 13 (1.5%).77 (4, 1.76) 31 Coronary revascularization 13 (15.5%) 157 (18.1%).81 (.64, 1.2).76 Hospitalization for angina 13 (1.5%) 18 (2.1%).72 (5, 1.47) 59 Subgroup Results Conclusion 1 EDTA-based chelation therapy reduces combined cardiovascular events in post MI patients (5-year NNT= 18) treated with optimal medical therapy. 7

8 TACT Chelation Results: Dismay at the AHA TACT: High-Dose Oral Treatment 3 caplets twice a day for the duration of the study. Vitamin A Vitamin C Vitamin D 3 Vitamin E Vitamin K Thiamin Niacin VitaminB 6 Folate Vitamin B 12 Biotin Panthothenic Acid Calcium Iodine Magnesium Zinc Selenium Copper Manganese Chromium Molybdenum Potassium Choline Inositol PABA Vanadium Citrus Flavonoids Double-blind active or placebo high dose vitamins were shipped from a central pharmacy to sites. Lamas GA, Goertz C, Boineau R, et. al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 212 Jan;163(1):7-12. TACT Vitamin Primary Endpoint Results Vitamins: HR (95% CI).89 (.75, 1.7) P = 12 High-Dose Vitamins 37% 34% Death, MI, stroke, coronary revascularization, hospitalization for angina Median follow-up 55 months

9 TACT Primary Endpoint: Factorial Groups EDTA Chelation/High-dose Vitamins vs. / HR (95% CI):.74 (7,.95) P = % Infusions/ Vitamins Infusions/High-Dose Vitamins EDTA Chelation/ Vitamins EDTA Chelation/High-Dose Vitamins Months 24since 3 randomization Endpoints EDTA Chelation and High-Dose Vitamins (N=421) Infusions and Vitamins (N=437) Hazard Ratio (95% CI) P-value Primary Endpoint 26% 32%.74 (7,.95).16 CVD, MI or stroke 9% 13%.66 (4,.99).46 Death 1% 11%.87 (7, 1.3) 81 Cardiovascular death (CVD) 5% 6%.75 (1, 1.37) 83 MI 5% 7%.71 (2, 1.21) 3 Stroke 1% 2% 4 (3, 1.42) 35 Coronary revascularization 14% 19%.67 (8,.94).19 Hospitalization for angina 1% 3% 9 (8, 1.31) 19 Conclusion 2 High-dose oral vitamins and minerals demonstrate an 11% reduction in cardiovascular events which is not statistically significant, yet this event reduction carries over to the combination of EDTA chelation + oral vitamins. 9

10 Conclusion 3 Compared with OMT + placebo/placebo, OMT + active/active demonstrates an enhanced reduction in clinical events (HR (95% CI):.74 (7,.95), P =.16) This reduction is of sufficient magnitude to be clinically significant (5-year NNT= 12) DM definition Self-reported diabetes Treated for diabetes Fasting blood glucose 126 mg/dl prior to enrollment These criteria expanded the population with diabetes from 538 to 633 patients, or 37% of the study subjects The expansion of the diabetes definition was decided prior to performing the resulting analysis. Primary Endpoint by infusion arm Diabetes EDTA Chelation vs. HR (95% CI): 9 (4,.79); P =.2 Bonferroni Adjusted: (9,.88); P =.2 RR = 41% NNT = 6.5 over 5 years CI (4.4, 12.7) Infusions EDTA Chelation Number at Risk: EDTA Chelation

11 Primary Endpoint TACT Kaplan-Meier Estimates of the Primary Composite Endpoint EDTA Chelation Therapy vs. Subset of Patients with Diabetes: Hx, Med Use or Baseline Glucose>=126 TACT Kaplan-Meier Estimates of the Primary Composite Endpoint EDTA Chelation Therapy vs. Subset of Patients without Diabetes (Hx, Med Use or Baseline Glucose>=126) Hazard Ratio 95% CI P-value (log-rank) EDTA: 9 4,.79.2 Hazard Ratio 95% CI P-value (log-rank) EDTA: , EDTA Chelation EDTA Chelation Number at Risk EDTA Chelation Number at Risk EDTA Chelation Diabetes Patients (633) No Diabetes (175) TACT Kaplan-Meier Estimate of the Primary Composite Endpoint EDTA Chelation Therapy vs. Superimposed Graphs: Subset of Patients with Diabetes & Subset of Patients without Diabetes Hazard Ratio 95% CI P-value (log-rank) EDTA: 9 4,.79.2 EDTA Chelation Number at Risk Death by infusion arm - Diabetes EDTA Chelation vs. HR (95% CI): 7 (6,.88); P =.111 Bonferroni Adjusted: (, 1.6); P = Number at Risk: EDTA Chelation

12 Conclusion 4 Patients with diabetes demonstrate enhanced efficacy with EDTA chelation. Compared with placebo, EDTA-treated patients demonstrated a 41% reduction in CV endpoints (p=.2), and a 43% reduction in total mortality (p=.11), This reduction is of sufficient magnitude to be clinically significant and worthy of consideration for further study or selective implementation (5- year NNT= 7). TACT Primary Endpoint in Diabetes Subgroup TACT Primary Endpoint in Diabetes Subgroup Infusions / Vitamins

13 TACT Primary Endpoint in Diabetes Subgroup Infusions / Vitamins Infusions / High-Dose Vitamins TACT Primary Endpoint in Diabetes Subgroup Infusions / Vitamins Infusions / High-Dose Vitamins EDTA Chelation / Vitamins TACT Primary Endpoint in Diabetes Subgroup Infusions / Vitamins Infusions / High-Dose Vitamins EDTA Chelation / Vitamins EDTA Chelation / High-Dose Vitamins

14 2/1/214 TACT Primary Endpoint in Diabetes Subgroup Infusions / Vitamins EDTA Chelation / High-Dose Vitamins EDTA Chelation/High-dose Vitamins vs. HR (95% CI): 9 (3,.75) P < Conclusions 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 This effect size is sufficient to put us at a crossroads When do you do yet another trial if you have results you believe? When the treatment is chelation therapy 14

15 What if the treatment had been a CETP inhibitor? What if the study had been negative? No new trial is needed, you have enough data 15

16 What s Really Next? Replicate results and extend the patient eligibility Work out mechanisms, particularly the heavy metal hypothesis Present the data: Scientific debate enhances the learning environment and informs the design of future trials References Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, Drisko JA, Lee KL. Design of the trial to assess chelation therapy (TACT). Am Heart J. 212;163(1):7-12. Lamas G, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, Lindblad L, Lewis EF, Drisko JA, Lee KL.. Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction. The TACT Randomized Trial. JAMA. 213;39(12): Lamas G, Boineau R, Goertz C, Mark DB, Rosenberg Y, Stylianou M, Rozema T, Nahin RL, Lindblad L, Lewis EF, Drisko JA, Lee KL.. Oral High-Dose Multivitamins and Minerals After Myocardial Infarction: A Randomized Trial. Ann Intern Med. 213;159: Escolar E, Lamas G, Mark D, Boineau R, Goertz C, Rosenberg Y, Nahin RL, Ouyang P, Rozema T, Magaziner A, Nahas R, Lewis EF, Lindblad L, Lee KL. The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 214; 7: