clinical benefit of edta chelation therapy in patients with diabetes in the trial to assess...
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Clinical Benefit of EDTA Chelation Therapy in Patients with Diabetes in the Trial to Assess Chelation Therapy
(TACT) Esteban Escolar, Gervasio A. Lamas, Daniel Mark, Pamela Ouyang, Allan Magaziner, Robin Boineau, Ralph Miranda, Christine Goertz, Yves Rosenberg, Richard Nahin, Richard
Nahas, Eldrin Lewis, Lauren Lindblad, Kerry L Lee
For the TACT Investigators
The National Center for Complementary and Alternative Medicine (U01AT001156) and the National Heart, Lung and Blood Institute
(U01HL092607) provided sole support for this study.
No disclosures to report
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 without evidence of benefit.
• In 2001, NCCAM and NHLBI released an RFA for a definitive trial of EDTA chelation
• TACT showed a statistically significant reduction of a combined cardiovascular endpoint (HR 0.82 [95% CI, 0.69-0.99]; p = 0.035) with an EDTA-based infusion regimen in patients with prior MI
• There was an interaction between chelation infusion and self-reported diabetes
• The present analyses provide greater detail on the effect of chelation therapy in patients with diabetes
Lamas GA, Goertz C, Boineau R , et. al. JAMA. 2013;309(12):1241-1250
Background
Design Overview
Chelation + high-dose vitamins
Placebo chelation + high-dose vitamins
Chelation + placebo vitamins
Placebo chelation + placebo vitamins
40 infusions at least 3 hours each; 30 weekly infusions followed by 10 maintenance infusions 2-8 weeks apart.
Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012 Jan;163(1):7-12.
Infusion components
Lamas GA, Goertz C, Boineau R, et. al. Am Heart J. 2012 Jan;163(1):7-12.
Chelation Infusion
Placebo Infusion
• disodium EDTA, 3 grams (adjusted by GFR)• 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
• Normal Saline• 1.2% dextrose, 500 mL
Inclusion Criteria
• 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
End points
Primary endpoint: Time to first occurrence of either• death from any cause, • reinfarction, • stroke, • coronary revascularization, or • hospitalization for angina
Secondary endpoint: Time to first occurrence of either• cardiovascular death, • reinfarction, or • stroke
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
Statistical Analysis
• Log-rank test – Comparisons between arms for clinical events.
• Intention to treat analysis
Treatment comparisons: • Cumulative event rates - Kaplan-Meier method • RR expressed as HR with 95% CI (Cox model) and
nominal p values are reported• Bonferroni adjusted confidence intervals and p-
values, adjusted for 9 different subgroup factors
Diabetes(N=633)
No Diabetes(N=1075) P-value
Age 65(59,71) 65(58,72) 0.784
Female (%) 19 17 0.280
BMI 31(28,36) 28(25,32) <0.001
CHF (%) 23 15 <0.001
PVD (%) 22 12 <0.001
HTN (%) 78 63 <0.001
Hypercholesterolemia (%) 85 80 0.013
CABG (%) 49 43 0.008
PCI (%) 56 61 0.040
Statin (%) 76 72 0.063
ACE or ARB (%) 73 58 <0.001
ASA/clopidogrel/warfarin 92 91 0.202
Fasting Glucose (mg/dL) 131(109,162) 97 (90,105) <0.001
Baseline characteristics of patients with or without Diabetes
For all continuous variables [median (25th, 75th)].
Chelation(N=322)
Placebo(N=311)
Age 65 (60,71) 66 (58,71)
Female (%) 17 21
BMI 31(28,36) 32(28,36)
Anterior MI (%) 40 36
HTN (%) 78 78
Hypercholesterolemia (%) 86 84
PCI or CABG (%) 85 78
Statin (%) 77 75
ACE or ARB (%) 73 73
ASA/clopidogrel/warfarin (%) 93 92
LDL (mg/dL) 81(63,105) 85(63,115)
Fasting Glucose(mg/dL) 129 (107,160)
134(109,165)
Baseline characteristics of patients with Diabetes by infusion arm
For all continuous variables [median (25th, 75th)]. p >0.05 for all comparisons
Placebo Infusions
Placebo 311 270 235 214 187 168 155 134 116 94 63
0 6 12 18 24 30 36 42 48 54 600
0.1
0.2
0.3
0.4
0.5
Months since randomization
Even
t R
ate
EDTA Chelation 322 286 262 243 217 198 187 177 157 126 74
EDTA Chelation
EDTA Chelation vs. Placebo
HR (95% CI): 0.59 (0.44, 0.79); P = 0.0002
Bonferroni Adjusted: (0.39, 0.88); P = 0.002
Number at Risk:
Primary Endpoint by infusion arm Diabetes
RR = 41%NNT = 6.5 over 5 years CI (4.4, 12.7)
Placebo 311 270 235 214 187 168 155 134 116 94 63 558 506 466 424 379 347 320 295 268 228 142
Placebo Infusions
0 6 12 18 24 30 36 42 48 54 600
0.1
0.2
0.3
0.4
0.5
Months since randomization
Ev
en
t R
ate
Number at Risk:
0 6 12 18 24 30 36 42 48 54 60
Months since randomization
No Diabetes
EDTA Chelation
EDTA Chelation322 286 262 243 217 198 187 177 157 126 74 517 474 441 407 371 339 324 299 270 232 155
DiabetesEDTA Chelation vs. PlaceboHR (95% CI): 1.02 (0.81, 1.28); P = 0.8768
EDTA Chelation vs. PlaceboHR (95% CI): 0.59 (0.44, 0.79); P = 0.0002Adjusted: (0.39, 0.88); P = 0.002
Primary Endpoint by infusion arm
0 6 12 18 24 30 36 42 48 54 600
0.1
0.2
0.3
0.4
0.5
Months since randomization
Even
t R
ate
EDTA Chelation vs. Placebo
HR (95% CI): 0.60 (0.39, 0.91); P = 0.0170
Bonferroni Adjusted: (0.32, 1.09); P = 0.153
EDTA Chelation 322 293 275 259 236 219 210 201 182 149 90
Placebo 311 276 252 231 206 190 180 161 139 117 79
Number at Risk:
Secondary Endpoint by infusion arm Diabetes
0 6 12 18 24 30 36 42 48 54 600
0.1
0.2
0.3
0.4
0.5
Months since randomization
Eve
nt
Rat
e
EDTA Chelation vs. Placebo
HR (95% CI): 0.57 (0.36, 0.88); P = 0.0111
Bonferroni Adjusted: (0.30, 1.06); P = 0.099
Number at Risk:
Placebo 311 293 275 250 227 205 195 174 151 128 83
EDTA Chelation 322 303 283 267 251 230 222 211 193 160 101
Death by infusion arm - Diabetes
Limitations
• Although this subgroup analysis was prespecified, subgroup findings, regardless of how robust they appear, must be considered hypothesis-generating
• A moderate number of patients withdrew consent, limiting somewhat the events that could be accrued and attributed during follow-up
Conclusions
• Post-MI diabetic patients age 50 or older on evidence-based medications demonstrated a marked reduction in cardiovascular events with EDTA-based chelation therapy
• These findings support the initiation of clinical trials in patients with diabetes and vascular disease to replicate these findings, and define the mechanisms of benefit
• They do not, as yet, constitute sufficient evidence to indicate routine use of chelation therapy for post-MI diabetic patients
This article is now available online inCirculation: Cardiovascular Quality & Outcomes
http://circoutcomes.ahajournals.org/content/early/2013/11/19/CIRCOUTCOMES.113.000663