By Robert J. Nardino, MD, FACP
"Chelation" comes from the greek word for claw. That fits just right with the popular notion that chelation therapy can snatch bad molecules from clogged arteries. Established as a treatment for heavy metal poisoning, chelation has been postulated as an alternative to the existing standard of care for the treatment of coronary artery disease (CAD).
Testimonials of dramatic improvement following chelation therapy continue to fuel a demand from patients with all forms of vascular disease. Although the extent of its use is unknown, one estimate put the number in the vicinity of 500,000 people per year in the United States;1 a Canadian study surveying patients who had undergone cardiac catheterization found that 8% had tried chelation.2 Despite greater attention to risk factor modification, CAD continues to kill half a million people annually in the United States, and its prevalence continues to rise. Therefore, it is crucial to determine if chelation is a viable treatment option. Currently, that question remains unanswered.
Pharmacology
The major active ingredient for chelation therapy is ethylenediamine tetraacetic acid (EDTA). EDTA comes in two forms—the disodium salt and the calcium disodium salt. The sodium salt chelates calcium—in fact, a rapid infusion may cause hypocalcemia, and is the form generally used for chelation therapy of atherosclerosis. It also chelates other polyvalent metals such as magnesium and zinc. The calcium disodium salt chelates divalent and trivalent metals, and is used predominantly for the treatment of acute and chronic lead toxicity. Both forms of EDTA are poorly soluble in water. After intravenous administration, EDTA has a half-life of 20-60 minutes. It is excreted predominantly by the kidney.
Mechanism of Action
The mechanism of action of chelation therapy for CAD remains controversial. Initially it was hypothesized that EDTA removed calcium from plaque. But other mechanisms have been postulated, because atheromatous plaques are not simply calcium and bone preferentially may give up the calcium removed by EDTA.3 These mechanisms include inhibition of platelet aggregation, free radical scavenging, and inhibition of matrix metalloproteinase activity, which may stabilize plaque.4 EDTA may reduce the oxidation of LDL.5 Finally, it also has been proposed that a reduction in serum calcium leads to vascular dilation.6
Technique
A single chelation treatment lasts from two to four hours. Anywhere from five to 30 treatments may be prescribed in the first month, with maintenance treatments recommended once monthly after this. The formulation recommended by the American College for Advancement in Medicine (ACAM) uses 50 mg/kg disodium EDTA with heparin, magnesium chloride, high-dose vitamin C, and additional B vitamins, along with lidocaine as a local anesthetic.7 The ACAM’s position paper on chelation therapy can be viewed at: www.acam.org/chelationtherapyinformation.php#intro.
Controversy
There exist some proponents of oral chelation therapy; however, no published data could be found to substantiate oral use, and the technique garners fervent criticism from many in the intravenous chelation therapy group.
Medicare and other health insurance providers do not reimburse for chelation therapy. In addition, in some locations, such as Oregon, insurance companies will not provide malpractice insurance for physicians who perform chelation therapy (www.acponline.org/journals/news/apr02/malpractice.htm).
It is clear that strong emotions surround the evaluation of chelation therapy. Proponents point to the uncontrolled, observational data they have accumulated and reported in the publication sponsored by the society that promotes chelation, the American College for Advancement in Medicine.10,11 However, there may be significant placebo effects attributable to this treatment. With each recent controlled trial that has failed to show the superiority of chelation over placebo, there have appeared vociferous letters denouncing the findings as biased.4,12-14 Remaining noticeably absent are studies conducted by chelation proponents appearing in peer-reviewed medical literature. Prior to the publication of the PATCH study (Program to Assess alternative Treatment strategies to achieve Cardiac Health), and because the previous randomized studies were not sufficiently powered to detect small differences, the National Institutes of Health, through the National Center for Complementary and Alternative Medicine (NCAAM), issued a request for grant proposals for a long-term study of chelation therapy.
Clinical Studies
Controlled trials concerning the efficacy of chelation therapy are few and far between. Ernst summarized the existing data on chelation for the treatment of CAD in 2000.8 Many observational reports appeared in the 1960s and indicate subjective improvement. A placebo-controlled trial published in 1963 involving nine patients with a clinical diagnosis of CAD indicated initial improvement at 12 weeks, but no statistical analysis was performed. A German study appeared only in abstract form in 1997, showing that in 16 patients with angiographically proven CAD randomized to EDTA or placebo, no difference was observed in exercise performance.
More recently, Knudtson et al published the results of the PATCH study , a randomized double-blind, placebo-controlled trial of chelation therapy.9 The investigators enrolled 84 patients with stable angina and CAD documented by cardiac catheterization. The intervention group received EDTA chelation therapy at a dose of 40 mg/kg for three hours, twice weekly for 15 weeks, followed by one treatment per month for three months. The control group received saline instead of EDTA with a similar treatment schedule. Both groups received oral multivitamins and treatment of risk factors according to American Heart Association guidelines. The main outcome measure was change in time to ischemia during treadmill testing done at baseline and again at 27 weeks. Secondary outcomes were exercise capacity by determination of anaerobic threshold and quality of life based on a series of validated instruments. In all three of these outcomes, chelation failed to produce a result that was superior to placebo.
Adverse Effects
The most common side effect of intravenous chelation therapy is burning at the infusion site. In fact, one report characterized the inability to undertake a blinded study of chelation therapy because of this side effect. Recent studies have used lidocaine at the infusion site to prevent this symptom and preserve blinding.15 Renal failure has been reported; renal tubular damage can result from high doses of EDTA, but not at the doses typically used for chelation therapy. If recognized early, the effects on the kidney are reversible. Only one patient in the Knudtson study dropped out because of a rise in serum creatinine (1.5 to 2.1 mg/dL).9 Hypocalcemia appears to be rare with the currently used protocol. Prolonged bleeding time, bone marrow depression, hypoglycemia, and death have been reported in association with chelation therapy.8
Contraindications include hypersensitivity to EDTA and anuria. Relative contraindications include pregnancy (potential teratogen) or existing hypocalcemia and hypokalemia, which can be worsened. Caution must be observed in patients with renal insufficiency or impaired myocardial contractility.
Other Effects
Calcium disodium EDTA is used to treat lead poisoning and intoxication by other heavy metals, and has been demonstrated to be effective in this regard.
Dosage and Formulation
EDTA is stored at room temperature, and must be diluted before use. The dose according to the ACAM protocol is calculated with consideration of creatinine clearance, but usually is 3 g. The infusion also includes: 20 meq sodium bicarbonate; 3 g vitamin C; 2.5 g magnesium sulfate; 2,500 units heparin; 2.5 mg folic acid; 100 mg pyridoxine; 1,000 mcg cyancobalamin; 1 mL B-complex-100 (optional, not always available); and lidocaine to relieve pain at the infusion site.
The infusion typically requires three hours and costs between $50 and $100. In the first month, patients usually receive from five to 30 treatments. Patients often are advised to continue preventive treatment once a month.
There is no specific licensure required to administer the therapy; because EDTA is approved by the Food and Drug Administration (FDA) for other indications, it can be employed for off-label uses. The ACAM provides training and essentially credentials practitioners for chelation therapy.
Conclusion
There are no data from properly controlled trials supporting the benefit of chelation therapy for patients with atherosclerotic diseases. The American Medical Asso-ciation, the American Heart Association, the Ameri- can College of Physicians, the American College of Cardiology, and the FDA have published statements recommending against the use of chelation therapy, citing no proven benefit.
A large NCCAM-sponsored study is planned, which should erase criticism about the insufficient power of prior studies.16 Definitive evidence of efficacy and safety would benefit millions of individuals, and additional evidence from a large randomized trial would help to answer these questions.
Recommendation
Current data do not support the use of chelation therapy for the treatment of atherosclerotic disease. In the hands of experienced practitioners, it appears to be relatively safe; however, patients with renal disease or congestive heart failure should proceed with caution. Patients wishing to try chelation therapy should be should be encouraged not to abandon proven therapies when indicated. v
Dr. Nardino is Program Director of the Internal Medicine Residency at the Hospital of Saint Raphael in New Haven, CT, and Assistant Clinical Professor of Medicine, Yale University School of Medicine.
References
1. Grier MT, Meyers DG. So much writing, so little science: A review of 37 years of literature on edetate sodium chelation therapy. Ann Pharmacother 1993;27: 1504-1509.
2. Quan H, et al. Use of chelation therapy after coronary angiography. Am J Med 2001;111:686-691.
3. Guldager B, et al. Effects of intravenous EDTA treatment on serum parathyroid hormone (1- 84) and biochemical markers of bone turnover. Dan Med Bull 1993;40:627-630.
4. Strassberg D. Chelation therapy for patients with ischemic heart disease. JAMA 2002;287:2077, discussion 2077-2078.
5. Frishman WH. Chelation therapy for coronary artery disease: Panacea or quackery? Am J Med 2001;111: 729-730.
6. Elihu N, et al. Chelation therapy in cardiovascular disease: Ethylenediaminetetraacetic acid, deferoxamine, and dexrazoxane. J Clin Pharmacol 1998;38:101-105.
7. Cranton EM. A textbook on EDTA chelation therapy. J Adv Med 1989;2:1-416.
8. Ernst E. Chelation therapy for coronary heart disease: An overview of all clinical investigations. Am Heart J 2000;140:139-141.
9. Knudtson ML, et al. Chelation therapy for ischemic heart disease: A randomized controlled trial. JAMA 2002;287:481-486.
10. Olszewer E, Carter JP. EDTA chelation therapy: A retrospective study of 2870 patients. J Adv Med 1989;2: 197-211.
11. Chappell LT, et al. EDTA chelation therapy for vascular disease: A meta-analysis using unpublished data. J Adv Med 1993;7:131-142.
12. Chappell LT, et al. EDTA chelation treatment for peripheral vascular disease. J Intern Med 1995;237: 429-432.
13. Chappell LT, et al. Chelation therapy. Circulation 1995;92:1350-1352.
14. Bell SA. Chelation therapy for patients with ischemic heart disease. JAMA 2002;287:2077, discussion 2077-2078.
15. Christensen K, Theilade D. EDTA chelation therapy: an ethical problem. Med Hypotheses 1999;53:69-70.
16. Jonas WB. Effectiveness of EDTA chelation therapy. Circulation 1995;92:1352.
Nardino RJ. Chelation therapy for coronary artery disease. Altern Med Alert 2002;5(9):107-110.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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