Chelation therapy for cardiovascular disease
To read more about chelation therapy click here.
Synonyms and keywords: Chelation therapy, EDTA, post-myocardial infarction, diabetes

# Overview
Chelation is a process by which an organic molecule with a negatively charged pocket complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. Chelation therapy, which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body. Common chelators include penicillamine, which binds copper and can be used to treat Wilsons disease, deferoxamine, which binds iron and is used in the treatment of thalassemia and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels, patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia, or sickle cell disease and transfusion acquired iron-overload, to name a few instances.
Ethylene diamine tetraacetic acid (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of atherosclerotic disease.  The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.

# Chelation Therapy and CVD
The use of chelation therapy as a treatment for atherosclerotic disease dates back to the 1950s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients. Later studies by Kitchell were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of chelation therapy for cardiovascular disease (CVD) tilted towards the negative.  To be fair, from the 1970s to 1990s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.
For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease. Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving endothelium-dependent forearm blood flow. A systematic review of four randomized clinical trials on chelation therapy and peripheral artery occlusive disease reported no benefit associated with chelation therapy. The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy.  Moreover, follow up was short and surrogate physiologic endpoints, such as walking distance, were used.  A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.  The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy.  Professional organizations recommended against chelation therapy. Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for cardiovascular disease and other diagnoses.
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function (creatinine 2.0 mg/dL or less).  The active treatment consisted of 40 infusions consisted of disodium EDTA combined with ascorbic acid, B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, stroke, MI, coronary revascularization, and hospitalization for angina. A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for statins in post-MI patients (NNT=16 for the secondary prevention of a major coronary event). The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.
TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and diabetes (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.440.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).  Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all postMI patients with diabetes, leaving open the clinicians choice to use this novel therapy in occasional, or non-routine patients.
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy. The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the NIH.

# Mechanism of Action
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine. Hence, chelation therapy results in the elimination of stored toxic and essential metals.  In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution.  Placebo did not increase the excretion of toxic metals.  Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%.  Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide  robust evidence linking toxic metals with cardiovascular disease. This evidence is strongest for lead and cadmium. Elevated blood concentration of lead is associated with increased all-cause mortality . Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine . 
Heavy metals may play a role in the development of cardiovascular disease through a number of different mechanisms. Heavy metals include transition metals such as cadmium, mercury, manganese, chromium, cobalt, nickel, iron, and copper, metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels.  Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids. Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability, endothelial cell dysfunction, and hypertension. Heavy metal exposure is also associated with genetic and epigenetic manifestations. Cadmium promotes atherosclerosis and endothelial dysfunction through multiple genetic changes. One of the mechanisms involves DNA strand breaks and damage with subsequent apoptosis in endothelial cells. Also, maternal lead exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of DNA methylation early in life.
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of chelation therapy may result from enhanced excretion of heavy metals, and subsequent reduction in processes listed above.  Additionally, in patients with diabetes, a reduction in the metal-catalyzed formation of reactive oxygen species, formation of advanced glycation end-products, and lipid peroxidation has been postulated. Metal detoxification in the context of diabetes possibly decreases inflammation and oxidative stress that characterize atherosclerosis. Recent research, including chelation-activity assays, indicates that many common diabetes drugs, such as metformin and aldose reductase inhibitors, could possibly have some chelating properties.
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use.  This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as ascorbic acid, B-vitamins and magnesium, thought to have a protective effect on endothelial cells, making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.

# Future Studies
TACT was a unique study with an unexpected result that could have vast public health implications.  In order to consider its broad applicability, the medical and scientific community require the results reproduced.  TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients.  If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.

# Side Effects
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy.  However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.
- Arrhythmias
- Autoimmune diseases
- Bone marrow
- Convulsions
- Depression
- Fever
- Heart failure
- Hypocalcemia
- Hypoglycemia
- Hypotension
- Prolonged bleeding time
- Renal failure
- Respiratory arrest
- Tetany
- Trace metal deficiency
- Vitamin deficiency

# Landmark Trials
- TACT
- TACT 2  (link to press release )