Chelation Therapy for the Treatment of Arteriosclerosis: A Medical Bypass?
Chelation Therapy for the Treatment of Arteriosclerosis: A Medical Bypass?
By Susan T. Marcolina, MD, FACP
Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
Chelation therapy consists of a series of intravenous infusions of the synthetic amino acid, ethylenediaminetetraacetic acid (EDTA). EDTA (chelator) is water-soluble and binds divalent and trivalent metal cations in the circulation to form a stable chemical ring structure that is then excreted renally. EDTA is an effective chelator of heavy metals and minerals such as lead, iron, copper, and calcium from the blood and has been approved by the FDA since 1953 for use in the treatment of lead poisoning. The fact that EDTA chelates extracellular divalent and trivalent metal ions with variable affinity (see Table) forms the basis for its clinical utility.1
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Table Metallic ions listed in order of greatest to least affinity with EDTA1 Iron+3 Mercury+2 Copper+2 Aluminum+3 Nickel+2 Lead+2 Cobalt+2 Zinc+2 Iron+2 Cadmium+2 Manganese+2 Magnesium+2 Calcium+2 |
CAD and Chelation Therapy
The idea for the use of EDTA for atherosclerotic disease stemmed from observations in the 1950s when it was noted that older patients undergoing EDTA therapy for chronic lead poisoning felt marked relief from angina pectoris.2 Since that time its use has been advocated for atherosclerotic peripheral vascular and coronary disease, with benefits reported in a small number of studies.3,4 Atherosclerotic disease in the form of coronary artery disease (CAD) is the No. 1 cause of death and disability for both men and women in the United States.5 The prevalence of CAD in the United States is estimated at 12.6 million persons, which includes 7.5 million who have had a myocardial infarction (MI) and 6.4 million with angina pectoris.6 Although no current data are available on the number of patients seeking chelation therapy, in 1993, Grier and Meyers estimated that more than 500,000 people in the United States undergo chelation therapy with EDTA each year.7
Pharmacology of EDTA
In the United States, commercially available salts include the disodium and the calcium sodium salts of EDTA. EDTA, in these formulations, is widely used as an in vitro anticoagulant for blood drawing and as an antioxidant stabilizer, synergist, and preservative for pharmaceuticals.8 Only calcium sodium EDTA is used in the treatment of lead poisoning.9 In chelation therapy for CAD, however, the most commonly used preparation in a protocol recommended by the American College for the Advancement of Medicine (ACAM) is disodium EDTA. EDTA formulations are poorly absorbed from the gastrointestinal tract. After intravenous infusion, however, EDTA is found primarily in plasma. It has a half-life of 20-60 minutes and is distributed in the extracellular fluid. It is primarily excreted through the kidneys, with about 50% excretion in one hour and 95% excretion within 24 hours.10
Chelation Therapy: Postulated Mechanisms of Action
Although the exact mechanism of action of EDTA chelation in atherosclerosis is unknown, Clarke et al initially postulated that EDTA, through its binding and renal excretion of extracellular calcium, lowers serum ionized calcium levels, resulting in the mobili-zation of calcium from the atherosclerotic plaques, thereby reducing atheroma formation.11 There is no clinical documentation of this phenomenon, however, and greater knowledge of the mechanisms of formation of the atherosclerotic plaque have made this theory unsupportable.12
Chelation therapy practitioners now contend that EDTA chelates both iron and copper, thus impairing free radical generation and lipid peroxidation, processes central to endothelial dysfunction and plaque formation.13,14 Duffy et al demonstrated that deferoxamine, an iron-chelating agent, improved endothelial function by improving nitric oxide (NO)-mediated endothelial vasodilatation in patients with CAD.15 However, in a non-randomized, unblinded study by Green et al, EDTA alone did not improve endothelial NO-dependent vasodilation in patients with CAD, even after 10 chelation infusions over 60 days.16 On the other hand, EDTA in combination with B vitamin supplementation did improve vasomotor responses and significantly decreased serum homocysteine levels.16 Despite this finding, Anderson et al, in a randomized, double-blind, placebo-controlled study, did not demonstrate an improvement in abnormal vasomotor responses in patients with CAD randomized to the EDTA therapy compared with the placebo patients, either in the short term or at six months, even though both groups were supplemented with oral multivitamin therapy, in accordance with the ACAM protocol.17
Other mechanisms that might account for the symptomatic improvement during chelation therapy reported by many patients with ischemic heart disease are arterial dilatation secondary to calcium channel blocking actions and stimulation of prostacyclin production. Additionally, although it has not been clinically documented, EDTA has been shown in in vitro studies to inhibit the activity of matrix metalloproteinases, a group of enzymes that degrade arterial extracellular matrix (ECM) components in human atherosclerotic plaques. Such inhibition may be important in the prevention of atherosclerotic plaque rupture.18,19
The ACAM protocol for the use of EDTA for CAD includes the use of intravenous magnesium, ascorbic acid, oral multivitamins (including vitamins A, C, E, B1, B2, B6, B12, niacin, folic acid, biotin, choline, panto-thenic acid, niacinamide, inositol, methionine, magnesium, potassium, manganese, zinc, chromium, and selenium), blood pressure and lipid monitoring, as well as dietary, exercise, smoking-cessation, and stress-reduction counseling, and other educational lifestyle interventions.20 Such cardiac risk factor modifications and the use of antioxidants have been shown to improve endothelial function and have merit in secondary prevention. Gokce et al showed in a randomized, double-blind, placebo-controlled study that both a single oral 2 g dose of ascorbic acid as well as a daily 500 mg dose for 30 days, improves brachial artery flow-mediated dilation in patients with angiographically proven CAD. The improvement was most pronounced in persons with abnormal baseline flow-mediated dilation.21 Schechter et al, in a randomized, prospective, double-blind, placebo-controlled trial, showed that six months of oral magnesium therapy in CAD patients significantly improves both brachial artery flow-mediated vasodilation and exercise tolerance as measured by the Bruce protocol.22
Thus, the vitamins and antioxidants prescribed along with the EDTA may be significant factors accounting for improvements noted in many of the uncontrolled studies and case reports.
Chelation Therapy Studies
A literature review by Ernst located 22 studies of chelation in patients with coronary disease. These studies had no control groups and only reported on development of subjective symptomatic improvements in patients. Two case reports that included objective angiographic data showed no evidence of benefit for chelation over placebo.23,24
Knudtson et al performed a double-blind, randomized, placebo-controlled trial over four years with 78 patients.25 The test group received weight-adjusted (40 mg/kg) EDTA chelation therapy or placebo twice weekly for 15 weeks and once monthly for an additional three months. Both placebo and test groups were able to significantly (P < 0.001) increase their exercise time to ischemia at the 27-week treadmill test compared to baseline. There was a tendency for modest increases in quality-of-life scores in both groups with significant but similar improvements in the exertional capacity component of the Seattle Anginal Questionnaire.26 During the year of follow-up, one patient in the placebo group had a documented MI and six other patients were hospitalized for worsening angina. Four of the patients subsequently required angioplasty and one underwent CABG. There was also an MI in the chelation group and nine patients were hospitalized for anginal exacerbations though none required angioplasty or CABG surgery. One chelation patient was withdrawn form the chelation therapy arm due to an elevation in serum creatinine levels that returned to baseline after 10 weeks. The study was not large enough to detect differences in the number of clinically evident ischemic events between the groups.
Van Rij et al conducted a double-blind, randomized, controlled trial of 32 patients with intermittent claudication randomized to an EDTA chelation treatment group (15 patients) and a control group (17 patients).27 Both groups received parenteral multivitamins in the intravenous solutions. Although both control and chelation groups had significant improvement in measured walking distances after the 10-week infusion period, there were no significant differences in measured walking distances and ankle/brachial indices (ABI) measured at rest and after treadmill exercise between the chelation and placebo groups.
Adverse Reactions to Chelation Therapy
The most common side effect reported is a burning sensation at the infusion site. Other side effects include infusion site phlebitis, prolongation of clotting times, hypotension, hypocalcemia, bone marrow depression, malaise, fever, headache, nausea, and vomiting. Renal toxicity was more common with doses of 5 g and is much less so with the 3 g dosage currently specified in the ACAM protocol for chelation.13
Guldager et al reported a statistically significant increase in the urinary excretion of lead, copper, zinc, and calcium in a group of 30 patients treated with disodium EDTA infusions vs. 30 control patients given saline infusions.28 Such augmented elimination of calcium and zinc may be associated with side effects of zinc depletion and bone decalcification and need to be carefully followed in patients undergoing a series of chelation infusions. Allain et al also noted that 24 hours after an infusion of EDTA, the urinary concentration of zinc was 15 times higher than normal in human subjects.29 Without replacement, the loss of this amount of zinc during the months a patient is undergoing two treatments per week or more will increase the potential for severe immunologic impairment and precancerous cellular mutations.
On the other hand, Meltzer et al observed 81 patients over a two-year period who received a total of 2,000 chelation infusions of 3 g doses of disodium EDTA as part of a preliminary investigation of its effectiveness in the treatment of CAD and found the most common adverse reactions to be mild hypocalcemia, localized infusional discomfort, and mild nausea and vomiting.30 They reported no problems with renal insufficiency, one episode of localized thrombophlebitis, two episodes of significant but short-lived systolic hypotension with symptoms, and no severe dermatitis or systemic allergic reactions. They reported no problems with bone decalcification but the serial X-rays of hands and wrists used to monitor for osteoporosis were not sensitive enough to detect significant problems.
Cost
The cost for chelation therapy, which typically ranges from $75 to $125 per treatment and requires a number of sessions, is not covered by most insurance companies.31
Chelation Protocol
The ACAM initially established a standardized protocol for the intravenous infusion of EDTA in 1989, which was revised in 1996. The protocol calls for the intravenous infusion of 500-1,000 mL of a solution containing 40 mg of disodium EDTA per kilogram of lean body weight (up to a maximum of 3 g), plus heparin, magnesium chloride, plus additional vitamins and minerals, and counseling regarding the therapeutic lifestyle interventions enumerated above. The intravenous infusion takes 3.5-4 hours and is given 1-3 times per week. The EDTA dosage and dosage intervals are adjusted according to the patient’s creatinine clearance.
The number of treatments required to achieve “optimal therapeutic benefit for patients with symptomatic disease” is said to range from 20 (minimum) to 30 (usually needed), or 40 (for full benefit), to as many as 100 or more intravenous infusions over a period of several years. The protocol states that “follow-up treatments may be given once or twice monthly for long-term maintenance, to sustain improvement, and to prevent recurrence of symptoms.”13,17,20
This protocol has been touted as a safe, effective alternative for conventional invasive treatments that include percutaneous translumenal coronary angioplasty and revascularization surgery. Proponents of chelation also point out that while surgical and angioplasty procedures are location specific, chelation therapy has the potential to treat the entire arterial systemic tree. The safety and efficacy of chelation therapy, however, had not been studied in a large, multicenter, randomized, placebo-controlled clinical trial until the currently ongoing Phase III Trial To Assess Chelation Therapy (TACT) study was initiated in March 2003.32
Trial to Assess Chelation Therapy: An NIH Phase III Trial
The National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute, components of the National Institutes of Health, are currently running a large-scale Phase III double-blind, placebo-controlled multicenter clinical trial to determine whether EDTA chelation therapy, high-dose vitamin therapy, or both are effective in secondary prevention of atherosclerotic disease. Thirty million dollars has been dedicated to support this study. The primary endpoint is a composite of all-cause mortality, myocardial infarction, stroke, hospitalization for angina, and revascularization procedures.
The TACT trial will enroll 2,372 patients aged 50 years and older who have had a heart attack (at least six weeks prior to the study start) at more than 100 research sites across the United States over five years. The trial was launched in March 2003. After baseline assessments, a total of 1,186 patients will be randomly assigned to receive 40 infusions of a standardized EDTA chelation solution and 1,186 will receive 40 placebo infusions. Then, each of the two groups will be randomized to receive high-dose vitamin/mineral supplements vs. low-dose vitamin/mineral supplements. All study participants will receive 30 weekly infusions of either chelation therapy or placebo solution followed by 10 bimonthly infusions and all will be followed until the end of the study to observe for significant clinical benefits or side effects.
The trial has thus far enrolled patients from 67 centers in 27 states.33
Conclusion
The TACT trial will provide important safety and efficacy information as to whether EDTA chelation therapy could be an important adjunctive therapy for persons with CAD. Until this information is available, however, chelation therapy cannot be recommended for secondary prevention. Patients with renal impairment should not undergo EDTA chelation therapy. The individual merits, however, of the lifestyle modifications and antioxidant vitamin and mineral supplementation advocated in the chelation therapy protocol have been shown to be important in the secondary prevention of coronary disease.
Recommendation
Randomized, placebo-controlled clinical trials have not shown chelation therapy to be more effective than placebo in the secondary prevention of atherosclerotic disease. Pending results of the TACT trial, it is important for all physicians who care for patients with coronary heart disease to implement and individualize a Cardiac Hospitalization Atherosclerosis Management Program to ensure appropriate use of medication, such as aspirin, extended-release cardioselective and specific nonselective beta blockers, angiotensin converting enzyme inhibitors, and statin drugs, proven to increase survival. Fish oil supplements containing eicosapentaenoic and docosahexaenoic acids reduce cardiovascular events in post MI patients by 20% and should also be considered in the pharmacologic secondary prevention armamentarium along with vitamin C and magnesium. Patients should also be encouraged to follow the therapeutic lifestyle changes recommended by the Adult Treatment Panel III.34-36 The Multicenter Life Demonstration Project demonstrated that improvements in lifestyle and psychosocial status diminished morbidity, mortality, and the progression of coronary disease for both men and women in different geographic regions across the United States.37
References
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