The identification of chelation as a chemical reaction originated in the late nineteenth and early twentieth centuries after discoveries by German and American chemists.¹,² The word chelation is derived from the Greek word, CHELE, to describe the grabbing by crab or lobster claws. The pinching mechanism of the chemical chelator can effectively grab and bind metals and minerals. This led to attaching the term chelation to the chemical reaction to describe incorporation of a metal ion into a heterocyclic ring structure.

Chelation used in clinical medical practice as a therapeutic intervention usually involves pharmaceutically derived compounds. It is important to understand that the term chelation is a general nonspecific term that defines a chemical equilibrium reaction between a charged metal ion and a complexing agent that results in a chemical bond between the two. The metal is said to be chelated and the complexing agent is the chelator, whether this is from a plant-derived source or any administered pharmaceutical agent. There are many types of chelators, both pharmaceutical and natural products, with wide-ranging chemical structures and differing affinities for metals and minerals. Biological systems in both plants and animals show many types of metal-binding proteins, such as metallothionein.³ These well-known chelators are central to the natural response of biological systems to toxic chemicals and, in humans, lead to inactivation of heavy metals and their eventual excretion by renal or biliary mechanisms.

Chelation is not a term that is specific to any one form of chelation therapy, although in some groups it has become synonymous with cardiovascular disease (CVD) treatment. To ascribe chelation therapy so narrowly to CVD is to misunderstand the broad views and rich variety of chelators. That said, this chapter will focus on ethylenediaminetetraacetic acid (EDTA) chelation therapy for CVD practiced for decades by integrative practitioners and currently under investigation in the TACT trials. For readers interested in understanding the use of chelation in other disorders and the widely available chelators, references are provided for more in-depth review.¹,³,⁴,⁵,⁶

In the twentieth century, therapeutic applications of chelation to remove heavy metals in humans was discovered.²,⁵,⁷,⁸ This was particularly valuable during World War II when chelation therapy was introduced as an antidote for arsenic-based poisonous gas exposures. This led to interest in chelation as a treatment of heavy metal poisoning, and chelation therapy has enjoyed basic science and clinical research through the ensuing years for treating heavy metal toxification. Chelation therapy for heavy metal intoxication has remained a mainstay in conventional toxicology when heavy metal poisoning is documented.⁷,⁹,¹⁰,¹¹,¹² However, conventional toxicologists have not supported the use of chelation therapy by integrative medicine practitioners in the treatment of CVD and heavy metal poisoning.²,¹³,¹⁴ Yet chelation therapy remains an important tool in integrative medicine when symptomatic patients with positive biological markers for heavy metal toxicity have positive test results with laboratory analysis.

EDTA is a pharmaceutically produced chelator first used in the 1930s in the German textile industry. EDTA was found to be helpful as a chelating agent to remove calcium during dye processing. In the 1940s, Martin Rubin, PhD, along with
chemist, Frederick Bersworth, discovered the biological effects of EDTA on calcium homeostasis, leading to its use in the laboratory as an anticoagulant.¹⁵ Rubin subsequently gained approval from the Food and Drug Administration (FDA) for EDTA use in humans with lead poisoning (CaEDTA) and hypercalcemia (disodium EDTA). Abbott Laboratories manufactured disodium EDTA under the tradename Endrate. It is this form of EDTA that is intravenously administered as chelation therapy that has become synonymous with the practice of chelation therapy for CVD.

Chelation therapy for the treatment of CVD dates to the 1950s. Two physicians, Albert Boyle and Norman E. Clarke Sr., separately published case reports that showed improvement in CVD status in patients who were receiving disodium EDTA during treatment of lead poisoning.²,¹⁶ The literature through this period is replete with numerous articles that include case reports, small clinical trials, mechanistic studies, observational studies, and anecdotal reports of benefits when disodium EDTA was administered in patients with atherosclerotic vascular disease (ASVD).²,¹⁷,¹⁸ This led to the historical hypothesis that disodium EDTA chelation in CVD decalcified diseased atherosclerotic vascular structures.

Clarke and colleagues treated a small number of patients with severe angina with disodium EDTA and found improved outcomes in 19 of 20 patients.¹⁶ Other small unblinded studies with limited assessment followed but seem to have less dramatic results.¹⁹,²⁰ Because of increasing controversy and variation in outcomes, conventional practitioners abandoned EDTA chelation.¹⁸ Chelation practitioners banded together to form medical organizations with the benefit of standardizing the infusions, doses administered, and rates of administration of disodium EDTA chelation.²,²¹,²²,²³,²⁴,²⁵,²⁶ Standardizing the administration of EDTA chelation succeeded over the ensuing years to provide a safe in-office practice, and it has been estimated that there have been millions of chelation infusions administered. Chelation practitioners develop protocols to make this therapy exceptionally safe.² For example, when EDTA chelation is infused rapidly, hypocalcemia may result. Of interest, there have been only 11 deaths attributed to EDTA chelation reported to the FDA, with 7 of those 11 deaths from prescription or pharmacy errors resulting in infusion of the incorrect form of EDTA.²⁷

Conventional physicians and cardiologists exhibited growing skepticism and hostility toward the practice of chelation therapy for CVD, but the practice continued to grow in the hands of integrative medicine practitioners. In 1963, disodium EDTA for CVD came under additional scrutiny when data published from a study with 10 male patients was combined with another trial with 81 patients, all with ASVD.²⁸ The conclusion of the paper was a recommendation for disodium EDTA chelation therapy to be discontinued as a treatment of CVD because of poor outcomes. Of note, across the 2 years of the study, the authors infused EDTA chelation therapy at a dose of 3 g for 2.5 to 3 hours in 2000 consecutive infusions without a reported adverse event. However, the report by Metzler et al. sparked debate on the part of the practicing chelation physicians calling into question the merits and pointing out problems with the report. The result of the Metzler et al. paper was to drive the practice of disodium EDTA for CVD underground, becoming the purview of integrative physicians only. As cardiologists warned patients against the practice because of the poor evidence base, integrative physicians continued EDTA chelation therapy for vascular disease to the present time. Case reports continued to be published in non-peer reviewed journals describing reversal of atherosclerotic plaques and reduction in symptomatic complaints of angina or claudication while receiving EDTA chelation. Conventional toxicologic research continued to focus on the use of EDTA for lead toxicity foregoing further research of chelation for CVD.⁴,⁶,⁷,²⁹,³⁰,³¹,³²

In 2002, the Cochrane Collaboration reviewed EDTA chelation therapy used in ASVD.¹⁷ The report included that there were no trials demonstrating the effectiveness of chelation therapy for coronary or cerebrovascular disease. The majority of trials to the time of the review focused on peripheral vascular disease, specifically investigating EDTA chelation as a treatment of intermittent claudication. The analysis proposed conducting randomized controlled trials in coronary and cerebrovascular disease because of the widespread ongoing use of the therapy. Subsequently, a small randomized trial (PATCH) was conducted in rolling 84 participants with known ischemic heart disease and angina, concluding that there was no evidence to support a beneficial effect of disodium EDTA chelation in CVD in this cohort.³³ The authors acknowledged that the trial was underpowered and therefore unlikely to show effect. Another confounding factor was that the placebo infusions contained IV vitamin C and this could not be excluded from having a beneficial effect.³⁴ Chelation therapy for CVD was about to enter into its next phase.