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Evaluation of chelation therapy for the treatment of CVD
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Use of chelation therapy as a treatment for CVD dates back to the 1950s. Chelation therapy uses a chelating agent to form complexes with multivalent cations such as calcium to promote excretion of the complexes from the body.
The chelating agent most often used in this process is IV ethylene diamine tetra acetic acid (EDTA), a synthetic amino acid first used medically to treat heavy metal toxicities. EDTA has several salt formulations, including disodium EDTA (edetate disodium), the salt most often used, albeit off-label, in chelation therapy for CVD. Disodium EDTA is often confused with calcium disodium EDTA (edetate calcium disodium), as both are often referred to as EDTA.
Theresa Page
Cynthia Sanoski
Calcium disodium EDTA is FDA approved for the treatment of acute and chronic lead toxicity and is also used for removal of other heavy metals. Disodium EDTA was previously approved by the FDA for the treatment of hypercalcemia and the management of ventricular arrhythmias associated with digitalis toxicity; however, the FDA removed these indications in 2008 due to safety concerns, including hypocalcemia, arrhythmias, renal failure and death, and the availability of other preferred treatment options for these conditions.
Several hypotheses for the potential mechanism of benefit of chelation therapy in CVD have been postulated. One proposed mechanism, now widely dismissed, is that calcium chelation may destabilize and dissolve atherosclerotic plaques. Another is that metal pollutants, such as lead, have a direct pathophysiological effect, leading to ischemic events; therefore, chelation may help to eliminate these metals. Another mechanism is that EDTA chelation, when given with ascorbic acid, may block endothelial damage by LDL cholesterol oxidation by transition metals.
Clinical trials in CVD
A small number of double blind, randomized controlled trials have assessed the efficacy of EDTA chelation therapy in patients with peripheral arterial disease during the past several decades. The majority evaluated the efficacy and safety of chelation therapy in patients with intermittent claudication; however, these studies primarily evaluated the effects of EDTA on surrogate endpoints, such as pain-free walking distance, ankle-brachial index and patients’ self-evaluation of symptoms.
In one study, 10 patients (mean age, 47 years) with intermittent claudication were randomly assigned 20 IV infusions of disodium EDTA 1.5 g or placebo (infusion duration and frequency of administration was not specified). After 10 of the planned infusions, the investigators observed improvement of exercise tolerance and ankle-brachial index in the EDTA group, but not in the placebo group. As a result, all patients received EDTA for the remaining 10 infusions in a single blind fashion. In another study, 153 patients aged at least 40 years with intermittent claudication were randomly assigned 20 infusions of disodium EDTA 3 g or placebo for 6 to 10 weeks. In a subgroup of 30 patients, no significant differences were observed between groups with respect to change in maximal walking distance or patients’ own evaluation of treatment effect after 10 infusions.
Data regarding the efficacy and safety of EDTA chelation therapy in patients with CAD are also sparse. A double blind, randomized controlled trial was conducted in 84 patients (mean age, 66 years) with CAD to assess the effects of EDTA chelation therapy on exercise parameters (time to ischemic electrocardiographic changes, maximum oxygen consumption and anaerobic thresholds) and quality of life. Patients were assigned 40 mg/kg of EDTA chelation solution (maximum of 3 g) or placebo twice weekly for 15 weeks and then once a month for a total of 33 infusions. No significant difference was observed between the groups regarding the indicated endpoints from baseline to week 27.
TACT was the first-ever double blind, randomized controlled trial to evaluate the efficacy and safety of chelation therapy in patients with a history of MI. The primary endpoint was a composite of all-cause mortality, MI, stroke, coronary revascularization or hospitalization for angina. Enrollment began in 2003 and was completed in 2010. Initial plans called for the enrollment of 2,372 patients during 3 years, but difficulties in enrollment led to a reduction in the sample size to 1,700 patients and an increase in median follow-up duration to 4 years. Temporary suspensions of the trial and investigations by the US Department of Health and Human Services’ Office for Human Research Protections and the FDA surrounding questions of informed consent and trial conduct at several clinical sites further complicated the trial’s progress. Because of the need for 11 interim analyses, a P value of less than .036 was required for statistical significance in this trial.
A total of 1,708 patients (median age, 65 years) were enrolled in TACT. With a two-by-two factorial design, patients were randomly assigned to IV disodium EDTA (up to 3 g; dose based on estimated glomerular filtration rate) or placebo, and then to an oral high-dose multivitamin and mineral supplement or placebo. For the chelation therapy, patients received 30 weekly infusions of disodium EDTA or placebo followed by 10 maintenance infusions administered 2 to 8 weeks apart. Each infusion was performed during a minimum of 3 hours.
After a median follow-up of 55 months, the primary endpoint occurred in 26% and 30% of patients in the chelation therapy and placebo groups, respectively (HR=0.82; 95% CI 0.69-0.99). Although the effect of chelation therapy on the individual components of the primary endpoint was of similar magnitude, none was statistically significant. Two patients in the chelation group and two in the placebo group experienced a severe adverse event, including one death in each group that was possibly or definitely due to study therapy. The incidence of hypocalcemia was significantly higher in the chelation group (6.2%) vs. the placebo group (3.5%).
Little research, big costs
Of the few randomized controlled trials before TACT that evaluated the effect of EDTA chelation therapy for PAD or CAD, only one reported outcomes in support of chelation therapy. These trials have been criticized for their small sample size, flawed randomization, inadequate blinding, inadequate reporting, variable methodologies and/or surrogate endpoints. Many practitioners had hoped that TACT would finally resolve the question of chelation therapy’s efficacy in reducing CV events. Although TACT found statistical significance in the primary composite endpoint, the upper limit of the 95% CI was 0.99. There was no significant difference in any of the components of the primary endpoint. In addition, 311 (18%) patients were lost to follow-up and 289 withdrew their consent. Because the results of the primary endpoint barely achieved statistical significance, this level of non-retention limits the overall interpretation of the results of this trial.
Overall, with so much criticism of the cost of TACT (more than $30 million) and questionable rigor, it is doubtful that a trial of this magnitude will be repeated. As of press time, there were no planned or ongoing trials for EDTA chelation therapy in CAD reported on ClinicalTrials.gov. It is also worthy to note that total out-of-pocket treatment costs for patients opting to undergo chelation therapy is significant, and exceeded $31 million in 2007. A single course of chelation infusions may cost up to $5,000 and is not covered by Medicare or most insurance plans. In addition, the most recent stable ischemic heart disease guidelines published in 2012 by the American College of Cardiology Foundation and American Heart Association do not recommend the use of chelation therapy, citing insufficient evidence for improving symptoms or preventing adverse outcomes in patients with stable ischemic heart disease. These guidelines further describe chelation therapy as “costly, time-consuming, can result in harm, and could result in patients failing to pursue proven treatment strategies.” Therefore, it is unlikely that chelation therapy will gain widespread acceptance in the medical community as an effective treatment for CVD anytime soon.
Disclosure: The authors report no relevant financial disclosures.