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Preface

This risk-benefit analysis is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify potential rejuvenation therapies and systematically evaluate their risks, benefits, and associated therapeutic protocols to create transparency.

Section 1: Overview 

Motivation

Ethylenediaminetetraacetic acid (EDTA) is a synthetic amino acid that can chelate metals (lead, iron, copper, calcium, mercury, arsenic, aluminum, chromium, cobalt, manganese, nickel, selenium, zinc, tin, and thallium) and metal ions.  Chelation is a process in which the reversible binding of a chelator to a metal ion forms a metal complex (in a redox inactive state), that can then be excreted by the kidney or liver.

EDTA is an approved medication for lead poisoning, hypercalcemia, and digitalis toxicity. The "off label" use of EDTA to prevent and/or reverse cardiovascular and other chronic diseases is widespread but still the subject of much debate.

It is hypothesized that EDTA chelation therapy acts to stabilize or reduce atherosclerotic plaques through the removal of metastatic calcium. Other proposed mechanisms of its beneficial effects include stimulation of parathyroid hormone (PTH), free radical scavenging, reduction of total body iron, membrane stabilization, prevention of epigenetic changes, decreasing platelet aggregation, and arterial dilatation due to calcium channel blocking effects. 

Key Questions 

This analysis seeks to answer the following questions:

• Which benefits result from EDTA chelation therapy? 

• Which risks are involved in EDTA chelation therapy (general and method-specific)?

• What are the potential risk mitigation strategies?

• Which method or combination of methods is the most effective for EDTA chelation therapy?

• Which of the available methods are safe for use? 

• What is the best therapeutic protocol available at the moment?

Impatient readers may choose to skip directly to Vascular Rejuvenation using EDTA#Section 6 for the conclusion and tips on practical application. 

Section 2: Methods

Analytic model

This RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development ( Sarac et al., 2012 ). 

Literature search

A literature search was conducted on Pubmed, Google Scholar, and the Cochrane Library using the search terms shown in Vascular Rejuvenation using EDTA#Table 1 . Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms.

Inclusion criteria: All studies performed in humans that used EDTA as a therapy to prevent or reverse cardiovascular or other chronic diseases were included. 

Exclusion criteria: We excluded preclinical studies from our analysis because of the large amount of human data available.

Table 1: Literature Search 

Recommended Reading/Viewing

As there are widely divergent views on the use of EDTA chelation therapy to prevent and/or reverse vascular disease we have chosen to include examples of the various standpoints. 

The following sites offer information on EDTA chelation therapy at a consumer level from a positive or neutral standpoint and are useful as an introduction to the topic:

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  • Unleaded: What the American Heart Association won't tell you about Heart Disease - youtube.com

  • EDTA Chelation Therapy: A Non-surgical Treatment for Heart Disease and Atherosclerosis - drcranton.com

  • Chelation Therapy - argylefamilychiropractic.com

  • Chelation therapy for heart disease: Does it work? - mayoclinic.org 

The following articles are examples of the negative viewpoint on chelation therapy that is currently found on many sites: 

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  • What Does Chelation Therapy Treat? - healthline.com

  • What is Chelation Therapy? - webmd.com 

  • What is Chelation Therapy? - trustedsupplementreviews.com
    

Abbreviation list

Section 3: Existing evidence

Summary of results from clinical trials (humans)

Our search of the Pubmed, Cochrane Library and Google Scholar databases identified  2179 papers. We screened the titles/abstracts and then performed a manual search of the reference lists of the selected papers. This resulted in the inclusion of 111 human studies in our analysis. The remainder were excluded due to duplication or lack of relevance.

The majority of the papers are observational studies (case reports/series, retrospective analyses) or open-label trials without a control group. Only 21 of the studies were randomized control trials (RCT). The level of evidence for the bulk of papers is, therefore, by definition, very low and the interpretation of data even in many of the higher-quality studies is questionable. It has been claimed by proponents of chelation therapy that there are more than 4600 reports supporting its use in  cardiovascular disease (Cranton, 2001). Additionally, the American Academy for Advancement in Medicine compiled 3539 abstracts on EDTA chelation (although many are animal or mechanistic studies) (Cranton, 2001). 

A few systematic reviews (Seely et al., 2005; Villaruz & Dans, 2002; Ernst, 2000) on the subject also exist but the authors used widely divergent inclusion criteria with the result that each review contains an analysis of different sets of data. We, therefore, chose to include the individual papers in our analysis rather than using the conclusions of these reviews. 

A Cochrane review, published in 2002, (Villaruz & Dans, 2002) concluded that there was insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of people with atherosclerotic cardiovascular disease and stated that such a decision must be preceded by large RCTs. 

A large multi-centre 2x2 factorial double-blind RCT known as the "Trial to Assess Chelation Therapy" (TACT) that took 10 years to complete was then conducted. The e xtremely positive results of this large, phase 3 clinical trial (n=1708) were published in 2013 and  have led to further large scale trials on chelation therapy, the results of which should be published by 2022 (TACT2, TACT 3a). 

Table 2: Clinical Trials 

Section 4: Risk-Benefit Analysis

Decision Model

Risk and benefit criteria

The decision profile is made of up risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and include the type, magnitude, and duration of the benefit as well as its perceived importance to the patient. The risk criteria are organized by category, type, severity, frequency, detectability, and mitigation. All are assigned numerical values: 

1 = low

2 = moderate

3 = high

The numerical values for both risk and benefit criteria are then summarized serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). Each benefit and risk criteria is assigned a weight/importance of 1 (low) 2 (medium) or 3 (high).

Weighting is independent of data sets and the final weights are based on consensus with justification based on the preceding columns of the table.

Score

Each category is assessed according to the performance of EDTA chelation therapy against the comparator (physiological ageing) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior) and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, whether it came from human or animal studies and whether methodological flaws, conflicting studies, or conflicts of interest (funding) by the authors are present. Evidence that is based on RCTs is initially assigned an uncertainty score of 1, evidence from open-label trials is assigned a score of 2, and evidence that is based on observational studies is assigned a score of 3. The uncertainty score is then adjusted by upgrading or downgrading using the above-mentioned criteria. 

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted using the uncertainty score. Weighted scores may be upgraded where the uncertainty of the evidence is low or downgraded where the uncertainty of the evidence is high. 

Benefit assessment 

Our analysis identified a total of 54 benefits that have been documented in human studies to date. 

Table 3: Benefit assessment  

Cardiovascular system

Reduced number of cardiovascular adverse events (total mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina)

The Trial to Assess Chelation Therapy (TACT) (n=1708) is the only phase 3 clinical trial to have assessed chelation therapy. The authors reported a 26% reduction in cardiovascular adverse events in patients treated with 40 EDTA infusions + vitamins as compared with double placebo (Lamas et al., 2013).

Myocardial infarctions (MI) were reduced by 23%, strokes by 23%, coronary revascularizations by 19% and hospitalizations for angina by 18% (Lamas et al., 2013).  As patients were already on optimal evidence-based medical therapy (statins, aspirin, ACE inhibitors (ACEi) etc...) the reduction represented a benefit beyond that which is being achieved by conventional therapies.

A subgroup analysis (Escolar et al., 2014) of participants with diabetes showed even greater benefits with a 15% (vs. 4%) absolute decrease in 5-year primary event rate (death, reinfarction, stroke), a relative reduction of 41% of a combined cardiovascular endpoint and a 52% reduction in recurrent myocardial infarctions. There is currently another large-scale trial in progress to verify the results (TACT2). Various explanations have been sought for the increased effect of EDTA chelation therapy in diabetics. There is considerable evidence suggesting the overproduction of reactive oxygen species (ROS) in diabetics (Pitocco et al., 2013). As well, iron excess and high levels of ceruloplasmin are associated with diabetes and both have been associated with cardiovascular disease (CVD) risk as well ( Ouyang et al., 2015 ). 

A third paper (Ujueta et al., 2019), analyzed a subgroup of the TACT patients that suffered from peripheral arterial disease (PAD) in addition to diabetes and found that the active treatment group had even more impressive 48% relative risk and 30% absolute risk reductions for cardiovascular adverse events.

Although there was no significant effect on mortality in the overall group, the study was not powered for this comparison. In the diabetic subpopulation, mortality was reduced by 43% and the absolute risk of mortality was even further reduced in the subgroup of patients suffering from both PAD and diabetes (24% down to 11% of participants).

To put the results of this trial in context, the chelation + oral vitamin group had a 5-year number needed to treat (NNT) of 12 (6.5 in diabetics) compared to a 5-year NNT for statin therapy as secondary prevention for cardiovascular adverse events of 15 (Peguero et al., 2014) and the NNT for commonly prescribed ACEi of 116 to prevent one cardiac death and 80 to prevent one cardiac infarction (Brugts et al., 2015). This means that 20% fewer people have to be treated with EDTA than with statins (one of the most widely prescribed compounds) in order to prevent one cardiovascular adverse event. 

The levels of various heavy metals were measured at baseline and again after receiving a 3-gram dose of EDTA in a subset of 20 patients who participated in TACT. Post-EDTA treatment, large increases of lead (3700%) and cadmium (750%) were measured in the urine ( Arenas et al., 2016 ) supporting the hypothesis that the removal of heavy metals may be responsible for some of the  beneficial clinical effects.

TACT was the first trial to measure cardiovascular adverse events as a primary outcome but another study also reported that 89% (58/65) patients referred for coronary bypass surgery no longer required it after chelation therapy (Hancke & Flytlie, 1993).

In contrast to the large body of evidence supporting a reduction in adverse cardiac events, we only identified two case reports stating that the need for cardiac catheterization was not positively impacted by EDTA therapy (McGillem, 1988 ; Magee, 1985). 

Decreased anginal symptoms

Several studies extending back over many years have reported a decrease in anginal symptoms following a series of EDTA infusions (Clarke et al., 1956;  Clarke et al., 1960;  Clarke et al., 1955