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EDTA Chelation Therapy for Coronary Artery Disease


Part 1

Release Date: April 30, 2001


RFA:  RFA-AT-01-004

National Center for Complementary and Alternative Medicine


National Heart Lung and Blood Institute

Letter of Intent Receipt Date:  July 18, 2001

Application Receipt Date:       August 29, 2001



The National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI) invite applications for a multi-site, randomized, double-blinded, placebo-controlled trial investigating the efficacy and safety of EDTA (ethylene diamine tetra-acetic acid) chelation therapy in individuals suffering from Coronary Artery Disease (CAD). It is estimated that more than 800,000 visits for chelation therapy were made in the U.S. in 1997. If chelation therapy is safe and effective in treating CAD it would represent a new therapeutic modality that would gain widespread application.   However, if chelation therapy is ineffective, these data will provide important information to the U.S. public and allow for informed decision making concerning continued use of EDTA for CAD.






CAD is the leading cause of mortality for both men and women in the United States. The prevalence of coronary heart disease is estimated at 12 million, including 7 million suffering from acute myocardial infarction and 6.2 million with angina pectoris (NHLBI 1998 Chartbook). More than 500,000 Americans die of heart attacks each year. Common conventional medical treatments for CAD include percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery, procedures that are invasive and costly.  


Chelation therapy has been used by some physicians for treatment of atherosclerosis, although compelling evidence indicating treatment efficacy is absent.


Chelation Therapy


Chelation refers to the formation of metal complexes by the bonding of a chelating agent or ligand with a metal to form a heterocyclic ring.  Initially, the medical use of chelating agents was to treat heavy metal poisonings, for example, British Anti-Lewisite (2,3-dimercaptopropanol) for

arsenical poisoning (1) and citrate for lead intoxication (2).  Another chelating agent, ethylene diamine tetraacetic acid (EDTA) was also used to treat lead poisoning in a young child (3) and following its initial approval by the Food and Drug Administration (FDA) in 1953, EDTA was used to treat hypercalcemia, other heavy metal poisonings (4-6), and metastatic calcification (7). 


Originally, it was a clinical observation that EDTA appeared to reduce symptoms of angina pectoris (8) and it was also noted that it affected cholesterol metabolism (9,10).  Subsequently, EDTA was advocated by some physicians to treat symptoms of atherosclerotic disease.  In some studies, clinical measures of efficacy such as exercise time, ankle-brachial index, and

arteriograms have been reported in addition to subjective data.  Chelation has been used most widely in peripheral vascular disease, but also in coronary artery disease, and cerebrovascular disease.  However, few controlled data are available that speak to the usefulness of chelation in the treatment of heart or vascular disease (11-17).


Pharmacology of EDTA


EDTA is a tetrabasic acid with 4 replaceable hydrogen ions.  Importantly, it is poorly soluble in water but it is soluble in alkaline hydroxides.  In the US, the commercially available salts are the disodium and the calcium disodium salts of EDTA.  In these formulations, EDTA is widely used as an in vitro anticoagulant for blood collection and as an antioxidant synergist, stabilizer and preservative for pharmaceutical preparations.  For chelation therapy, the most widely used formulation is a protocol recommended by the American College for Advancement in Medicine (ACAM) (18) that includes disodium EDTA and magnesium chloride. This formulation has yet to be tested in rigorous randomized controlled trials.


EDTA chelates various divalent metal ions with differing affinities. It is poorly absorbed from the gastrointestinal tract. Following intravenous administration, EDTA is found primarily in plasma.  It is distributed in the extracellular fluid, and it does not appear to penetrate cells (Dr. Mike: that’s why it should be administered with lipophilic catalysts that act as carrier agents for transport across and into cell membranes).  Only about 5% of the plasma concentration is found in spinal fluid. The half life is 20-60 minutes.  It is excreted mainly by the kidney, with about 50% excretion in one hour and more than 95% within 24 hours.  Almost none of the compound is metabolized.  Treatment with EDTA has a low incidence of side effects.  The most common side effect reported is a burning sensation experienced at the infusion site. Relatively rare adverse effects include phlebitis at the infusion site, malaise, fever, hypotension, hypocalcemia, headache, nausea, vomiting, diarrhea, insulin shock, bone marrow depression, prolonged prothrombin time and cardiac arrhythmia. Cases of renal toxicity have also been reported. 


Possible Mechanisms of Action of EDTA


Mechanisms involved in the pathogenesis of atherosclerosis include proliferation of smooth muscle cells, abnormalities of lipid metabolism, and endothelial dysfunction.  However, historically, calcium deposition was also believed to be important in the development of atheroma.  There is an age-associated increase in calcium deposition in the arterial wall.  The

hypothesis is that EDTA will chelate calcium from atheromatous plaques and thus favorably alter the plaque and the arterial wall, for example by altering endothelial function (19).  Other postulated mechanisms of EDTA action include a) inhibition of platelet aggregation (20), b) stimulation of parathormone (PTH) release that in turn mobilizes calcium from plaques and reduces progressive calcification, c) an antioxidant effect by complexing with transitional metals thus interfering with free radical production and lipid peroxidation, d) effects on serum iron (21), and e) transient lowering of serum cholesterol.  Some of these hypotheses may be valid.


Studies of EDTA Chelation Therapy in Arteriosclerosis


Coronary Artery Disease


The use of chelation therapy in coronary artery disease is limited to 12 descriptive studies and four randomized control trials (RCT) (7, 22-33).  Although each of the descriptive studies reported a reduction in angina, they are uncontrolled clinical observations or retrospective data, typically with small numbers of patients.   Two of the RCT were underpowered to detect a

difference, a third RCT did not publish a final paper, and the fourth noted exercise mprovement but was limited to 10 subjects.


Peripheral Vascular Disease


Most of the EDTA chelation studies have focused on peripheral vascular disease and are a combination of RCTs and descriptive studies.  These RCT’s have not demonstrated significant benefit but they were underpowered to detect a small effect and each trial has been criticized by some for methodological problems. Observational reports of the use of EDTA in peripheral vascular disease suggest that chelation can increase exercise duration but in the absence of a

placebo control group, spontaneous symptomatic improvement cannot be excluded

(7,8,11-17, 22, 25, 29-32, 34-45).


Cerebrovascular Disease


The use of EDTA chelation has been reported in patients with cerebrovascular disease.  The claims of efficacy with EDTA therapy are based on subjective clinical improvement and in some studies, improved cerebral perfusion or reduction in degree of carotid stenosis (22,25,26,30,34, 36,39,46-48).  Typically, however, the patient populations were small and had a variety of

cerebral diseases;  most importantly, the studies were without appropriate controls, and in some, there was criticism of methodology.  Particularly in the older data, the observations tended to be subjective and descriptive.  There are no appropriate randomized trials of EDTA in the treatment of cerebrovascular disease.   


References cited in this RFA can be obtained at







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