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From the Townsend Letter
May 2014

Protocol Controversies for Treating Cardiovascular Disease with EDTA Chelation Therapy
by L. Terry Chappell, MD, and Jeanne A. Drisko, MD, CNS
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Introduction
The Trial to Assess Chelation Therapy (TACT) is the only large, randomized clinical trial to provide statistically significant evidence that EDTA chelation therapy with high-dose multivitamins can reduce future cardiac events in patients with known cardiovascular disease.1,2 TACT utilized the published protocol that is used by organizations such as the American College for Advancement in Medicine (ACAM), the International College of Integrative Medicine (ICIM), the American Board of Clinical Metal Toxicology (ABCT), and the International Board of Clinical Metal Toxicology (IBCMT), all of which teach physicians how to administer the therapy and/or test them to provide certification.3
   
TACT used an intravenous dose of 3 g of disodium EDTA with magnesium, adjusted downward if kidney function was compromised, 7 g of vitamin C, 500 cc of sterile water, and several minor additives, all infused over a minimum of 3 hours.1,2 (See Table 1.) The published protocol is more flexible, allowing for 1.5 g to 3 g of disodium magnesium EDTA over no more than 1 g per hour and varying amounts of vitamin C, as long as the osmolality of the treatment solution is not hypotonic and not so hypertonic as to cause problems. Calcium EDTA has also been used in various forms with claims of effectiveness for vascular disease. The use of calcium EDTA, especially in the oral form, to treat cardiovascular disease has been criticized by the teaching organizations mentioned above. Concerns have also been raised about high doses of vitamin C, which becomes a prooxidant instead of an antioxidant at certain levels.4
   
The purpose of this article is to discuss the rationale, evidence, and experience of physicians who are acknowledged experts in the use of EDTA for treating cardiovascular disease. We hope to clarify whether calcium EDTA should be used to treat vascular disease and how much EDTA and vitamin C are effective and safe to use.

The Published Protocol
TACT used the 3 g basic dose of disodium EDTA with magnesium to treat patients who had a history of documented myocardial infarction. The basic protocol for TACT is shown in Table 1. The 3 g dose for disodium EDTA has been taught for years, and many doctors who provide intravenous chelation therapy use it routinely. However, there is evidence that a lesser dose might be just as effective.6-9 As a result, a substantial number of treating physicians use the lesser dose, based on these reports. Obviously, a lesser treatment time is more convenient for patients. Neither dose puts the kidneys at risk as long as the required rate of administration is followed. For patients with congestive heart failure, a lesser fluid volume for the treatment might be advantageous.

Table 1: Infusate Used in TACT
Component                                   Amount
Na2EDTA.........................................3 g
Magnesium chloride...........................2 g
Procaine HCl................................ 100 mg
Heparin..................................... 2500 units
Ascorbate (vitamin C)........................7 g
KCl..................................................2 mEq
Na bicarbonate............................840 mg
Pantothenic acid.......................... 250 mg
Thiamine......................................100 mg
Pyridoxine....................................100 mg
Sterile water........................... To 500 mL

The mixture of components given in TACT was based on committee consensus bewteen the TACT investigators and representatives of the chelating community. The agreed-upon solution was selected as the representative mixture that had been in use. The amount of EDTA administered to the trial participants was tailored to the individual renal function based on the Cockgroft-Gault equation.1-3

Chappell and Stahl performed a meta-analysis of studies showing objective improvement for patients with cardiovascular disease treated with intravenous EDTA chelation therapy.5 Nineteen published studies involving 22,765 patients met the inclusion criteria. All of these studies used the 3 g dose of EDTA with one exception. Olszewer and Carter treated 2482 patients with the 1.5 g dose, and 2379 improved.6 In the meta-analysis, 87% of patients improved, and there was a correlation coefficient of 0.88 between improvement in vascular function and treatment with EDTA. Patients of the physician who used the 1.5 g dose did as well as those from the other sites combined.
   
Chappell and associates did a follow-up meta-analysis of 32 unpublished reports on 1241 patients.7 1086 or 88% showed measurable improvement. 778 patients were treated with the 1.5 g bottle. A comparison of the 1.5 g and 3 g doses in this study showed almost identical results.
   
Born and Geurkink published a retrospective, randomized study comparing patients with peripheral artery disease treated with the 3 g dose of EDTA to those treated with the 1.5 g dose.8 20 treatments were given to 15 patients in each group. Those treated with the lower dose improved using Doppler ultrasound by an average of 123%. The patients in the 3 g group improved by an average of 70%. The results were statistically significant. One patient treated with 1.5 g improved 715%. That patient was omitted from the study as an outlier.
   
Chappell and associates compared 220 vascular patients treated with a basic course and maintenance chelation with matched controls from the literature.9 An average of 58 treatments were given. Subsequent cardiac events were much less in the EDTA-treated group. The patients treated with the 1.5 g dose had virtually the same results as those with the 3 g dose.
   
An in vitro study published in Surgery in 1962 showed the mobilization of calcium from atherosclerotic plaque with EDTA in the laboratory.10 The results demonstrated that the longer the tissue is exposed to EDTA, the more calcium was removed. To our knowledge, this finding has not been confirmed in vivo.
   
Blaurock-Busch observes that the German Chelation Society approves both a 2 g and 3 g dose.11 Gordon wrote the first American Academy of Medical Preventics (AAMP) chelation protocol in 1972, based on the work of such pioneers as Clark and Lamar. It was not published, but it was used in coursework for many years. He listed the EDTA dose of 50 mg/kg. Cranton's 1989 textbook refers to a maximum of 3 g dose, except for large patients who could receive up to 5 g at 50 mg/kg. The textbook was updated in 2001.12 Rozema's protocol for EDTA lists both a 3 g and 1.5 g dose, as does van der Schaar's 2012 textbook.3,13 The latter has a maximum of 4 g for large patients. All of these protocols insist on an infusion rate of disodium EDTA not faster than 1 g per hour to avoid overloading the kidneys.
   
Because of TACT, the best evidence for treatment of vascular disease with intravenous disodium EDTA lies with the 3 g dose. However, the published studies cited above that compare the 3 g dose with the 1.5 g dose show the latter to be as effective. As noted, one study showed the 1.5 g dose to be more effective for peripheral vascular disease. Future large clinical trials will be necessary to determine the lowest amount of EDTA that can produce the best outcome in cardiovascular disease.

Mechanisms of action for EDTA
Proposed mechanisms of action for EDTA chelation therapy have been documented, but no consensus exists as to which mechanism(s) are most important to treat vascular disease.14 It is well known that both disodium EDTA and calcium EDTA can remove heavy metals. Such metals as lead, cadmium, and mercury increase the risk of vascular diseases by increasing free radical activity.15 Reduction of free radicals by EDTA infusions reduces inflammation, which might lesson the likelihood of the rupture of unstable plaques.16 The clot that occurs as a result of this rupture is the accepted mechanism for most myocardial infarctions and strokes. A small study by Chappell and Angus showed a reduction of brachial artery stiffness with chelation.17 Iron deposits have been found in macrophage foam cells, which further increase free radicals and inflammation. Excessive copper also increases free-radical activity. EDTA chelates both iron and copper.18
   
Lowering blood calcium levels with intravenous boluses of disodium EDTA can inhibit platelet aggregation for weeks at a time.19 Intravenous EDTA has been proposed as a safer substitute for clopidogrel to prevent clotting after inserting drug-eluting stents.20 The anticlotting effect is likely to be an important mechanism for chelation's cardiovascular benefits. Selye demonstrated harmful deposition of calcium in soft tissue when a sensitized individual is exposed to a new challenge after a suitable interval.21 The drop in serum calcium that occurs almost immediately upon IV infusion of disodium EDTA stimulates parathyroid activity. Parathormone mobilizes calcium from soft tissue deposits, but the effect is irregular. Although there are case reports that plaque can be reduced with disodium chelation, studies have not shown a predictable improvement in lumen size for arteries blocked with plaque. It is possible that the calcium reduction cascade stabilizes vulnerable plaques, but this also has not been proved.22,23
   
High doses of magnesium are put into the intravenous treatment solution, which prevents adverse effects from the brief drop in calcium levels. Improved levels of intracellular magnesium might reduce irritable foci that cause arrhythmias and lower blood pressure. To prevent progressive calcium depletion, it is important that IV infusions of disodium EDTA be given no more often than 2 to 3 days per week, with at least 24 hours between treatments. With 60 years of use of intravenous disodium EDTA for vascular disease, no fatalities have been attributed to EDTA when the protocol has been followed. However, there have been isolated fatalities when disodium EDTA was administered by rapid IV push.
   
Nitric oxide (NO) is an important signaling molecule that is antiatherosclerotic. NO production declines with age and is worse with a high-fat diet. Lead inhibits NO formation. EDTA not only removes lead but also independently increases NO production.24 This might be an important mechanism for improved circulation for both disodium EDTA and calcium EDTA.
   
Vitamin K2 also might help remove metastatic calcium from arterial walls. It has been suggested as an oral supplement to augment the decalcifying effect of disodium EDTA.25 However, vitamin K2 is not currently included in the chelation therapy protocol.

Calcium EDTA
Intravenous calcium EDTA is approved for removing lead and is used to treat accumulations of other toxic metals. Since there is no reduction of serum calcium as is seen with disodium EDTA, certain mechanisms that are proposed for treating vascular problems do not apply. Specifically, metastatic calcium is not mobilized and platelets are not inhibited.
   
Oral, sublingual, transdermal, and rectal EDTA all consist of calcium EDTA. Oral EDTA is only about 5% absorbed. Rectal EDTA might be absorbed as much as 35% to 37%.26

Intravenous calcium EDTA is used widely as a challenge test and a treatment for toxic metals. It was used in a small study by Lin that showed that nondiabetic patients with moderate kidney disease might progress less rapidly with EDTA treatment than without.27 Chen and associates showed that diabetic nephropathy in the presence of high lead levels progressed at a slower rate than controls when their lead levels were reduced and kept under control with 1 g calcium EDTA treatments IV.28 High levels of lead have been shown to be associated with lower blood pressure and an increased risk of vascular disease.29 Reducing the lead burden might result in improved blood pressure and better circulation to the kidneys. However, without a drop in serum calcium, decalcification of the arterial wall is highly unlikely. The many published studies showing improvement in vascular disease, including TACT, all have used disodium EDTA with magnesium.
   
Gordon has proposed that calcium EDTA combined with lecithin and other nutrients improves blood viscosity, and he cites the work of Lowe and others.30 One might expect this to be the case since lavender-top tubes with EDTA are used to anticoagulate blood drawn from patients for testing. However, the EDTA used for that purpose is potassium EDTA (K2EDTA), not calcium EDTA. We were unable to find evidence that calcium EDTA reduces platelet activity directly. One mechanism for inhibition of platelet aggregation is a depletion of calcium ions. However, another probable mechanism that applies to calcium EDTA is its stimulation of the production of NO. Several oral nutrients that can lesson platelet aggregation, such as vitamin E and gingko, can be given orally along with calcium EDTA.
   
Cranton points out on his website a potential danger of oral chelation.31 Some toxic metals that are ingested might not be absorbed into the body if calcium EDTA is present, but many more essential minerals will also not be absorbed. Depletion of zinc, chromium, copper, manganese, and other minerals can reduce antioxidant defenses and endocrine function. Cranton stresses the importance of the rapid decrease in both toxic metals and calcium with disodium EDTA. This occurs extracellularly, since EDTA does not enter the cells. A reequilibration results so that calcium is mobilized as described above and toxic metals are brought out of storage in the bone, brain, and fat cells.
   
Calcium EDTA is widely sold and advertised as an ingredient in various nutritional supplements. Claims of effectiveness for calcium EDTA in treating vascular disease are often made based on research that was done for intravenous disodium EDTA. Calcium EDTA and disodium EDTA are two separate compounds that act on calcium differently in the body. Although useful mechanisms of action might apply for calcium EDTA, we did not find any clinical trials that support the use of calcium EDTA for treating vascular problems.
   
Van der Schaar's textbook describes many toxic metals and chelating agents.13 DMSA, DMPS, and the two forms of EDTA are commonly used in clinical practice at this time. DMSA is available orally and is used to chelate lead and mercury in adults and children. DMPS is a compounded substance for oral or IV use, mostly for lead and mercury, but it is not an FDA-approved medication. DFO is sometimes used parentally for iron overload, but serial phlebotomies are generally more effective. D-penicillamine can be helpful as a challenge test and occasional treatment. These medications can be used in combination if the prescribing physician is experienced. The two forms of EDTA are broader chelators and are especially effective for lead. EDTA has perhaps the weakest affinity for mercury. If mercury is elevated with a challenge test, it might be prudent to treat with DMSA or DMPS before prescribing intravenous EDTA. Maintaining good levels of beneficial minerals is important no matter what chelation agent(s) is/are prescribed. Treatment with DMSA or DMPS reduces free radical activity by binding and excreting heavy metals, which might be beneficial. However, we did not find any clinical trials that have studied either one as a treatment or preventative for vascular disease.

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