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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:

•  

  • 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: 

•  

  • 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;  Casdorph, 1981; Olszewer & Carter, 1988;  Boyle & Clarke, 1961; Maniscalco & Taylor, 2004; Evers, 1979; Robinson, 1982; Goonasekera et al., 2010). 

The earliest case report series (n= 20, 22) used high doses  (5 g per infusion) of disodium ethylene diamine tetraacetic acid (Na2EDTA) and patients reportedly experienced a "high" level of symptom relief ( Clarke et al., 1956; Clarke et al., 1955) following an average of 35 treatments. These patients were followed for up to two years.

A slightly later case series (n=76) in which patients received a reduced dose of Na2EDTA (3 g for 15 sessions) reported that 87% of patients experienced 90-100% symptom relief (Clarke et al., 1960). Similarly, a retrospective analysis (n=10) reported clinical improvements in 90% of subjects (Boyle & Clarke, 1961). 

Two open-label trials (n=18,13) (Casdorph, 1981;  Goonasekera et al., 2010) reported reduction or resolution of anginal symptoms in 84-88% of patients. 

Two large retrospective analyses also reported positive results in the treatment of angina. The first (n=2870) identified a "marked" improvement in 77% and a "good" improvement in 16.5% of patients with ischemic heart disease (Olszewer & Carter, 1988) where the term "marked" was defined as an initially positive stress test becoming negative and patients remaining symptom-free while off all medication. The second paper (n=3000) reported improved coronary circulation in all cases of angina, which was characterized by the patient having no need for vasodilators after the 5th infusion ( Evers, 1979).

The only trial in our analysis that used EDTA in the form of suppositories (in combination with antibiotics) rather than infusions also reported that angina was decreased or completely resolved in 84% ( 16/19)  of subjects (Maniscalco & Taylor, 2004). 

Contrary to the very positive results seen in the observational studies, a placebo-controlled double-blind randomized control trial (DB-RCT) (n=84) found no evidence to support a beneficial effect of chelation therapy in patients with stable ischemic heart disease (Knudtson et al., 2002). The negative conclusions in this study were based on exercise and quality of life measurements, however, fewer chelation patients subsequently required interventions, compared with the control group. According to data presented in the paper on clinical events during a follow-up period of one year, 5 placebo group patients required angioplasty or bypass surgery while none of the treated group did (Knudtson et al., 2002).

Improved ECGs

Several articles reported various types of improvements in the cardiac conduction system following EDTA chelation therapy (Clarke et al., 1956; Hancke & Flytlie, 1993; Li & Chen, 2017; Cheraskin, 1991; Boyle & Clarke, 1961; Riordan et al., 1988; Robinson, 1982). 

The early papers (between 1956-1987) are of low evidence quality and contain only general observations. One case series reported that ECGs reverted completely back to normal in 30% (6/20) of patients following 15-60 Na2EDTA treatments (Clarke et al., 1956) while  two studies simply report that "improvements" in ECGs occurred in about 70% of patients (Robinson, 1982; Boyle & Clarke, 1961). 

More specific ECG changes are mentioned by three papers, two of which identified a significant decrease (about 7%) of the QRS complex duration following 20 EDTA treatment infusions (Cheraskin, 1991; Riordan et al., 1988). A third article found  less ST depression in 69% (175/253) of patients following 30 EDTA infusions (Hancke & Flytlie, 1993).

The highest level of evidence on this topic comes from a case-control study (n=254) that showed the rate of abnormal ECGs in lead-exposed individuals was decreased from 44.9% to 33% after 6 months of EDTA therapy (Li & Chen, 2017). 

Improvements in the symptoms of PAD (intermittent claudication, wound healing, extremity temperature, pain, quality of life)

The results of the many observational studies on PAD (Clarke et al., 1960; Clarke et al., 1955; Hancke & Flytlie, 1993; Olszewer & Carter, 1988; Clarke et al., 1960; Godfrey, 1990; Ujueta et al., 2019) are overwhelmingly positive. 

Early retrospective analyses noted, "unusual symptom relief" (Clarke et al., 1955) and that pain at rest was invariably alleviated (Clarke et al., 1960). 74% of patients experienced 90-100% relief of intermittent claudication (IC) after 15 treatments with EDTA (Clarke et al., 1960) and all patients increased their pain-free walking distance and showed increased warmth and improved colour of their extremities (Clarke et al., 1960).

91% of patients in a retrospective analysis showed an increase of at least 5-fold compared to their baseline walking distance (Olszewer & Carter, 1988). A later retrospective analysis (n=262) reported improvements in the vast majority of patients in walking distance (87%), wound healing (70%), and extremity temperature (80%) (Hancke & Flytlie, 1993). Other papers were more general and simply reported "improvements" in 93% (25/27) patients with vascular disease (Godfrey, 1990). 

A very recent case report of a patient facing a double lower leg amputation due to exhaustion of all other treatment options reported complete resolution of the critical limb ischemia, pain, and healing of ulcers and gangrene (Ujueta et al., 2019). The excretion of toxic metals increased following EDTA chelation therapy, supporting the heavy metal chelation hypothesis. The authors also reported that they were unable to discount the possibility that arteries were decalcified (Ujueta et al., 2019).

An open-label trial on patients with both diabetes and critical limb ischemia (n=10) reported that all patients that had ulcers or gangrene at baseline, showed complete resolution of the wounds following 40 infusions as well as a 76.5% median improvement in pain scores and a 351% improvement in quality of life scores (Arenas et al., 2019 ).

One DB-RCT also reported positive results on walking distance in PAD patients ( Olszewer et al.,1990). Following 10 EDTA infusions, the treatment group doubled their walking distance, compared with essentially no change in the placebo group. Following the 20th infusion, the EDTA group walked nearly three times the distance. When the placebo group was crossed over to receive EDTA treatments, they improved approximately 100% ( Olszewer et al.,1990 ). 

A couple of studies have concluded that EDTA chelation therapy has no effect on IC. A Danish DB-RCT that produced two often-cited papers (n=153) (Sloth-Nielsen et al., 1991; Guldager et al., 1992), found that there was no significant change in maximal walking difference, ankle/brachial index, or arteriograms following EDTA therapy. However, the data shows that chelation patients actually improved 100% more than controls ( drcranton.com ). The study has been criticized in at least 4 journals and also by the Danish Committee on Scientific Dishonesty (Chappell & Janson, 1996).

A second DB-RCT also concluded that the improvement in walking distance was not significantly different between the chelation group (60%) and the control group (59%) (van Rij et al., 1994). However, chelation patients improved 78% more than controls and there was a significant increase in the pulsatility index. Raw data from the study revealed that 26% of the EDTA group achieved >100% improvement in walking distance (compared with 12% of controls). Following treatment, the ankle/brachial index was abnormal in only 6% of the EDTA group compared with 35% of controls. Additionally, van Rij's trial claimed to be placebo-controlled but actually used two chelating solutions, one with EDTA and the other with thiamin and ascorbate. The changes in the EDTA group may have reached significance with a true placebo (Chappell & Janson, 1996).

The TACT3a clinical trial on EDTA chelation in patients with critical limb ischemia (and diabetes) is underway and results are expected in 2022. 

Increased ankle/brachial index/pedal artery pulsation/skin perfusion pressure

Observational studies reported a 22% average improvement in ankle/brachial index scores (Cheraskin, 1991) and improved pedal artery pulsation (Evers, 1979). A retrospective analysis identified improvements in 82% (215/262) of patients with IC (Hancke & Flytlie, 1993). 

An open-label trial reported that in subjects who had severe claudication at baseline, pedal pulses were restored almost to normal (Maniscalco et al., 2004).

A second open-label trial reported a trend towards improved plantar skin perfusion pressure that narrowly missed significance (p=0.06) (Arenas et al., 2019). Pressures increased from 22 mmHg up to 46 mmHg following 20 infusions.

In contrast, two trials concluded that the ankle/brachial index remained unchanged following EDTA therapy ( Guldager et al., 1992; Sloth-Nielsen et al., 1991; van Rij et al., 1994). 

Decreased need for amputation/vascular surgery

A retrospective analysis reported that 89% (24/27) patients referred for surgical amputation of the lower extremity avoided surgery after receiving EDTA therapy (Hancke & Flytlie, 1993) and a case report series (n=4) noted that all 4 patients who had been referred for vascular surgery as a final treatment option did not require it (Casdorph, 1983 (chapter 11)). The clinical status of all 4 patients was improved significantly and they were ambulating normally at the one-year follow-up (Casdorph, 1983 (chapter 11)). 

A recent case report of a patient facing a double lower leg amputation due to exhaustion of all other treatment options also reported that amputation was avoided after a series of EDTA infusions (Ujueta et al., 2019).

However, another case report found no improvement following EDTA therapy and the patient subsequently required surgery (Magee, 1985). 

Decreased aortic stiffness (Pulse wave velocity)

A case-control series reported that pulse wave velocity (PWV) decreased significantly following 25 treatments with EDTA chelation therapy in all (n=43) patients. The initial PWV was 11.7 m/s and it decreased to 9.0 m/s following treatment (Van der Schaar, 2014). 

The assessment of aortic PWV, a measurement of the stiffness of the aorta is one of the most common noninvasive measures of arterial function and is predictive for cardiovascular disease events and all-cause mortality in subjects free of overt cardiovascular disease (Duprez, 2014). 

Decreased blood pressure

Many studies reported a decrease in systolic blood pressure (SBP) following treatment with EDTA, seven of which reported the actual values: 

The remaining studies either reported simply that SBP was lower following treatment or the proportion of patients that showed a reduction in SBP. 

Lead is an established risk factor for hypertension (Navas-Acien et al., 2007; Navas-Acien et al., 2008 ). Substantial evidence supports the role of lead in reducing the bioavailability of nitric oxide and promoting oxidative stress (Vaziri & Khan, 2007). Lead-induced hypertension has been shown to be reversible, either through the use of a chelating agent or by antioxidant treatment (Vaziri & Khan, 2007).

In support of the "heavy metal" hypothesis, a case-control series showed the number of lead-exposed workers with abnormally high blood pressure (BP) decreased from 30% at baseline to 15% following 6 months of EDTA therapy (Li & Chen, 2017).  A cohort study also identified a  reduction in systolic BP following 20 EDTA infusions, from 138 mmHg to 123 mmHg that was particularly prominent in patients with a higher than normal lead level (Born et al., 2012). 

Improved endothelial function

Improved endothelial function was reported by two studies (Van der Schaar, 2014; Green et al., 1999). A case-control series (n=43) reported that endothelial function was improved in all patients following 25 EDTA infusions but was still abnormal (Van der Schaar, 2014). Overall, the aortic augmentation index (Aix) decreased from 26.8% to 11.5% (abnormal = > 10%). Endothelial function is inversely correlated with the Aix (McEniery et al., 2006). 

An open-label trial (n=8) that measured forearm blood flow (FBF) responses following treatment with EDTA or EDTA + B vitamins found a significant increase in FBF in response to acetylcholine (Ach) following the combined treatment, indicating an endothelium-dependent process (Green et al., 1999). Resting FBF was 2.7 mL/100mL forearm/minute and increased to 11.31 mL/100mL forearm/minute following the Ach challenge in the saline-infused patients. In subjects that had received EDTA treatment, FBF increased to 15.21 mL/100mL forearm/minute while patients that had received oral vitamins plus EDTA exhibited an increased FBF of 19.67 mL/100mL forearm/minute. 

There is evidence that endothelial dysfunction is largely due to the inactivation of nitric oxide (NO) by oxygen free radicals, rather than a decrease in NO production (Green et al., 1999) providing an explanation as to why the combination of B vitamins + EDTA showed an intensified effect compared to the anti-oxidant action of EDTA alone. It has also been shown that lead may cause endothelial dysfunction through the inhibition of nitric oxide synthase (NOS), decreasing NO production (Peguero et al., 2014) thus indicating another possible mechanism by which EDTA could improve endothelial function. 

Increased work capacity/exercise tolerance

Several studies reported increased work capacity/exercise tolerance after a series of EDTA infusions ( Hancke & Flytlie, 1993; Van der Schaar, 1989; Olszewer & Carter, 1988; Olszewer et al., 1990; Evers, 1979).

Improvements in energy levels and work capacity were noted by 87% of patients (Hancke & Flytlie, 1993) and a c ase-control study (n=111) found that all chelated patients improved their exercise tolerance ( Van der Schaar, 1989 ) after a course of EDTA therapy. 

Two large retrospective analyses (n=2870, 3000) reported that approximately 90% of patients increased their maximal walking distance (Evers, 1979; Olszewer & Carter, 1988) (at least 5 times baseline in the second study). A small DB-RCT found that maximal walking distance doubled following 10 EDTA infusions, and tripled following the 20th EDTA infusion (Olszewer et al., 1990). When the original placebo group was crossed over to receive EDTA, they also increased their walking distance by 100%. 

A more recent open-label study reported that subjects increased the number of steps they could walk from 250 up to 1700 and the number of steps they could climb from 10 to 40 before experiencing anginal symptoms (Goonasekera et al., 2010).

In contrast, four trials reported no significant change in work capacity/exercise tolerance following EDTA therapy ( Sloth-Nielsen et al., 1991 ;  Guldager et al., 1992 ;  van Rij et al., 1994 ;  Knudtson et al., 2002 ; Diehm et al., 1986 (unpublished study)).

The first two papers are based on the same clinical trial, by a group of Danish cardiovascular surgeons, with admitted bias against chelation. The trial has been criticized because the baseline characteristics of the two groups were not well matched (the placebo group was significantly healthier). When the 6-month study was complete, the EDTA group had increased their maximum walking distance by 51% while the placebo group increased only 23.6%. 

In the second trial ( van Rij et al., 1994 ), the maximal walking distance (MWD) in the EDTA group increased by 25.9% while in the placebo it increased by 14.8% and was not statistically significant. However, there was an outlier in the placebo group that walked almost 500 m more than at baseline. This subject's data changed the placebo group from a decrease in MWD to an increase.

In the third trial ( Knudtson et al., 2002 ), the authors came to negative conclusions with regard to EDTA's effect on exercise time to ischemia, exercise capacity and quality of life measurements, but they also reported that none of the treated group required surgical interventions while 5 of the placebo group did ( Knudtson et al., 2002 ). 

The fourth trial was funded by a German pharmaceutical company Thiemann, AG. A group of patients were given a series of 20 EDTA infusions and compared to "placebo" that was actually Bencyclan, a vasodilator and antiplatelet agent. The results of the trial were not published but were presented at the International Congress on Arteriosclerosis in Melbourne, Australia, 1985. The study reported that the EDTA group increased their walking distance by 70% and the placebo group by 75% (Diehm et al., 1986). However, 12 weeks later, EDTA patients' continued to increase, reaching 182% ( Cranton, 2001 ).

The complete data showed that 4 patients in the EDTA group exhibited more than a 1,000 m increase in pain-free walking distance. However, this data disappeared before the results were made public as the company had reserved the right to edit the final results and chose to exclude those 4 patients as "outliers". With the inclusion of those 4 patients, the pain-free walking distance of patients treated with EDTA actually improved 400% - 5 times that of the "active" placebo ( Bencyclan ) ( Cranton, 2001 ).  

Decreased need for medication (nitroglycerin or insulin)

Several studies specifically mention that subjects were able to reduce or discontinue medications following a series of EDTA infusions (Hancke & Flytlie, 1993; Lamar, 1964; Evers, 1979; Jackson & Riordan, 1995; Rudolph & McDonagh, 1999). 

Of 207 patients with ischemic heart disease who used nitroglycerin, 189 reduced their consumption following EDTA treatments (Hancke & Flytlie, 1993) and most of them were able to discontinue use completely. 

Two case reports also mention that patients were able to gradually reduce or eventually discontinue blood pressure medications following EDTA therapy (Jackson & Riordan, 1995; Rudolph & McDonagh, 1999). 

Two retrospective analyses reported that many diabetic patients were able to reduce their insulin dose (Lamar, 1964; Evers, 1979). 

Decreased arterial stenosis

Six studies reported a widening of the vessel lumen at various sites in the body following EDTA therapy (Cheraskin, 1991; Holliday, 1996; Rudolph & McDonagh, 1990; Rudolph et al., 1991; Rudolph & McDonagh, 1993; Rudolph & McDonagh, 1999).

One study measured an 18% decrease in arterial stenosis by oculocerebrovasculometry following 28 EDTA infusions in patients with cerebral artery occlusion. The mean pretreatment stenosis was 28% and following therapy, the average score decreased to 10% (Cheraskin, 1991).

A study that evaluated restenosis following carotid endarterectomy found a 10% reduction in the degree of stenosis of the internal carotid artery with an accompanying decrease in both the systolic and diastolic velocities in chelated patients ( Holliday, 1996).

A case report noted that a previously 98% obstructed right internal carotid artery was only 33% obstructed as measured by ultrasound following EDTA chelation therapy (Rudolph & McDonagh, 1990). 

An open-label trial (n=30) reported that 100% of patients showed improvements on carotid ultrasound with an overall decrease of arterial stenosis of approximately 20.9% (Rudolph et al., 1991). The subgroup of patients with an initial stenosis >70% demonstrated an even greater decrease (41.6%). 

A case report that compared pre and post-treatment arteriograms found that coronary artery stenosis improved by 36% following EDTA treatment ( Rudolph & McDonagh, 1993).

Another case report found that renal artery stenosis was improved by more than 40% (Rudolph & McDonagh, 1999) and flow velocity through the renal artery decreased from 206 cm/s to 113 cm/s (approximately normal range). 

Decreased shear motion in the carotid artery

A case report found that abnormal shear motion in the carotid artery disappeared following 30 EDTA infusions (Rudolph & McDonagh, 1990). 

Improved coronary artery calcification scores

A trial combining long term antibiotic and EDTA treatment found that the coronary artery calcification score (CAC) was reduced by an average of 14% during a 4-month trial which is striking because CAC scores are known to increase by more than 20% annually (Maniscalco & Taylor, 2004). Every second patient showed improvement in their cardiac vasculature as assessed by the same CAC scoring machine in the hands of experienced (blinded) radiologists. 

Reduced heart rate

An open-label trial (n=50) reported an approximately 9% decrease in heart rate (Cheraskin et al., 1984).

Improvements in arrhythmias

A case series (n=58) showed that chelation therapy, by inducing hypocalcemia, had positive effects on the conducting system of the heart where pathological. Arrhythmias present included premature ventricular contractions, atrial fibrillation, heart block, ventricular tachycardia (VT), atrial flutter, and atrioventricular dissociation. Chelation therapy abolished or sharply diminished ventricular premature contractions in 67% (12/18) of patients and terminated VT in 2 patients as well as showing positive effects on the pacemakers (Soffer et al., 1961). 

Central nervous system benefits

Improved emotional health

An open-label trial (n=139) reported a 27% overall decrease in symptoms related to poor emotional health based on the Cornell Medical Index Questionnaire (McDonagh et al., 1985). Subset data analysis showed that feelings of tension decreased by 50%, depression by 49%, anger by 46%, inadequacy by 41%, sensitivity by 37% and anxiety by 23%. The authors speculated that an overall enhancement in circulation and its attendant improvement in cellular nutrition may be important variables. 

Decreased residual damage following strokes

Four studies reported that EDTA chelation therapy led to improvements in status post-stroke (Clarke et al., 1960; Olszewer & Carter, 1988; Clarke et al., 1960; Evers, 1979). All were case reports or retrospective analyses lacking control groups. 

In the earliest studies, EDTA therapy showed good results for symptoms of acute paralysis, senility, and tinnitus and excellent results in patients with vertigo. However, long term paralysis was only slightly affected. Patients were followed up for 37 months on average (Clarke et al., 1960a; Clarke et al., 1960b). 

A retrospective analysis (n=3000) reported improvements in amnesia, confusion, aphasias and motor coordination following treatment with a series of EDTA infusions and oral multivitamins/mineral supplements (Evers, 1979). 

A large retrospective analysis (n=508) reported "marked" improvement in 24% and "good" improvement in 30% of subjects suffering from cerebrovascular and other degenerative cerebral diseases ( Olszewer & Carter, 1988 ). Patients also received vitamins B, C and magnesium in the infusion and took an oral combined multivitamin, mineral and trace element preparation.

Epidemiological studies have indicated that elevated levels of heavy metals including lead (Pocock et al., 1988), mercury ( Garcia Gomez  et al., 2007 ), arsenic ( Wang et al., 2007 ), and cadmium (Peters et al., 2010) are associated with an increased risk of stroke. Lead may damage the endothelium, inducing microvascular dysfunction leading to changes in blood flow (Lin et al., 2018) and is associated with intracranial atherosclerosis ( Lee et al., 2009 ) .

Improved hearing

Two retrospective studies reported that hearing was improved following EDTA chelation therapy ( Clarke et al., 1955; Hancke & Flytlie, 1993). Improved hearing was self-reported by 65% of subjects (Hancke & Flytlie, 1993). 

Improved vision

Three studies reported improved vision (Hancke & Flytlie, 1993; Al-Hity et al., 2018; Rudolph et al., 1994). The first study (n=470) was a retrospective analysis in which 60% of subjects reported improved vision following EDTA chelation therapy (Hancke & Flytlie, 1993).

The second study was a retrospective analysis of patients (n=89) that were managed by topical EDTA chelation for band keratopathy (Al-Hity et al., 2018). Na2EDTA eye drops were applied and then the calcifications were removed. Visual acuity was maintained or improved in 79.8% of subjects. At 581 days, 28.1% showed localized recurrence of calcium but only four cases required repeat EDTA chelation (Al-Hity et al., 2018). 

A case report of a 59-yr old woman with AMD reported remarkable changes in visual acuity following 30 infusions of EDTA that remained constant at a one year follow up (Rudolph et al., 1994).

Tinnitus/vertigo

Three retrospective studies reported decreases in tinnitus and vertigo (Hancke & Flytlie, 1993; Clarke et al., 1960; Clarke et al., 1960). The improvements in vertigo were judged as "excellent" in one study (n=25) (Clarke et al., 1960). Symptoms of vertigo were also improved in 76% of subjects in another study (Hancke & Flytlie, 1993). The resolution of tinnitus was also reported by the studies but no data was provided.

Migraine

One retrospective analysis reported the disappearance of migraines as a "bonus" side effect of treatment ( Hancke & Flytlie, 1993). 

Increased cerebral blood flow

Following 20 EDTA infusions, an open-label trial (Casdorph,1981) showed increased cerebral blood flow in 14/15 patients with a medical history of cerebral blockage. 

Improved cognition and orientation/reduced signs of senility

Three observational studies (Casdorph, 1981; Clarke et al., 1960; Evers, 1979) reported improvements in cognition and/or orientation following EDTA therapy.

Decreased fatigue

An open-label trial (n=139) that assessed fatiguability using the Cornell Medical Index Health Questionnaire reported a 39% reduction in the mean fatigue score following 26 EDTA infusions (3g + oral multivitamin/trace mineral supplementation) given over a period of 61 days (McDonagh et al., 1984). 

Improvements in Parkinson's disease and manganese-induced Parkinsonism

A case series (n=7) of patients with manganese-induced Parkinsonism found that symptoms markedly regressed in 4 patients following treatment with CaNaEDTA and slightly improved in one more (Hernandez et al., 2006). A retrospective analysis (Evers, 1979) mentions that Parkinson's symptoms decreased following treatment with EDTA but provides no details.

Improvements in multiple sclerosis and neurodegenerative diseases

Patients with high levels of aluminum that underwent EDTA chelation therapy (22-34 sessions) and oral vitamin/trace mineral supplementation showed reduced fatigue and disability ( Fulgenzi et al., 2015). A case report also found that multiple sclerosis (MS) was improved following chelation therapy (Fulgenzi et al., 2012).

Improved memory

A retrospective analysis reported that 67% of subjects felt their memory had improved after receiving 30 Na2EDTA infusions over 3-4 months (Hancke & Flytlie, 1993).

Other chronic diseases

Scleroderma

A retrospective analysis of 4 patients with scleroderma reported that 3 showed "marked" and one "good" improvement following 20-40 treatments with Na2EDTA (Olszewer & Carter, 1988). However, another study of 4 patients with scleroderma found that prolonged (6 months) treatment with Na2EDTA had no effect on clinical condition (Mongan, 1965).

Improvement in chronic diseases/geriatric symptoms

An open-label trial of patients with significant chronic disease (average of 31.7 complaints) demonstrated a 15% decrease in clinical symptomatology that varied according to organ system. The best results were seen in the musculoskeletal system (31%) and the least effects in the GI and urinary systems (11%) (McDonagh et al., 1985). 

A retrospective analysis of 384 patients that were chelated for vascular-related geriatric symptoms such as asthenia, numbness, falls, dizziness, vertigo, tinnitus, and cognitive problems found that 75% of patients had a "marked" improvement, while 18% had a "good" recovery (Olszewer & Carter, 1988). 

Decreased risk of cancer mortality

An observational study (n=231) that followed up a group of subjects that had been treated with EDTA and controls found a 90% reduction in cancer mortality after an 18 year follow-up period. At that point, only 1.7% of the treated group had died of cancer compared with 17% of the untreated group (Blumer & Cranton, 1989).

Musculoskeletal System

Improvements in calcific tendonitis/arthritis 

Three studies reported improvements in arthritis and/or calcific tendinitis following EDTA treatment ( Cacchio et al., 2009;  Lamar, 1964; Evers, 1979).

A clinical trial that used single-needle mesotherapy (Na2EDTA) for three weeks in combination with ultrasound and 15% EDTA gel reported that calcifications disappeared completely in 62.5% of the patients in the treatment group and partially in 22.5%. The patients in the control group displayed a partial disappearance of 15% and none had a complete disappearance (Cacchio et al., 2009).

The second paper is a case report of a 54 yr old man with painful calcific tenosynovitis of the left shoulder, both palpable and visible on x-ray (Lamar, 1964). After 15 sessions of EDTA, he reported excruciating pain at the shoulder and many gravel-like pieces were palpable and visible on x-ray. Therapy was continued and after 30 sessions, there was no pain or calcification detectable. 

The third study was a retrospective analysis of 3000 patients that noted "great improvement" in arthritic patients (Evers, 1979). 

Decreased disc protrusion

A case report found a 60% decrease in the size of a recurrent disc herniation according to MRI following a series of 21 EDTA infusions and prolotherapy (Rudolph & McDonagh, 1992). EDTA therapy has been reported to be effective in various types of arthritis but often requires "boosters" because it doesn't address the underlying process.

It is believed to remove microscopic calcium deposits but doesn't affect joint stability. Prolotherapy causes fibroblastic proliferation leading to a strengthening of the ligamentous attachments and a return to normal stability. The combined use of EDTA and prolotherapy is synergistic, resulting in greater effects than either therapy alone (Rudolph & McDonagh, 1992). 

Metabolism and biochemistry

B12, GSH, oxLDL, ROS levels

Two studies that combined EDTA infusions with either a specialized combination product or standard multivitamin/trace mineral supplements measured an increase in vitamin B12 and GSH levels and a decrease in ROS, oxLDL, and homocysteine in both groups (Fulgenzi et al., 2014; Fulgenzi et al., 2015). The group that received the specialized combination product exhibited slightly better results. 

Increased platelet volume

An open-label trial (n=85) reported that 85% of patients had an increase in mean platelet volume after EDTA infusions. The mean platelet volume increased by 0.5 femtoliters (Rudolph et al., 1990).

Decreased lead and cadmium levels

Several studies measured lead levels before and after EDTA chelation therapy (Lin et al., 2002; Chen et al., 2012; Lin et al., 2001; Jackson & Riordan, 1995). 

One RCT reported that following EDTA chelation therapy, mean blood lead levels of the subjects in the active treatment group decreased to 3.7 µg/dl and their body lead burdens declined significantly to 46 µg, whereas in the control group blood lead levels 5.6 µg/dl and body lead burdens 116.3 µg were unchanged (Lin et al., 2002). 

A single-blind randomized control trial (SB-RCT) also reported that blood lead levels were lower in chelated patients 3.8 vs 6.8 µg/dL as were body lead burden 46.0 vs 151.3 µg (Chen et al., 2012). 

Another trial showed that following EDTA chelation therapy the body lead burden in the study group decreased from 198 to 39.2 µg ( Lin et al., 2001). 

A case report on the treatment of essential hypertension with EDTA therapy found that lead levels gradually decreased with treatment according to urine lead tests ( Jackson & Riordan, 1995).

An open-label trial reported that all patients had detectable cadmium and lead levels in their baseline, pre-infusion urine and that these levels increased by 292% and 3733% respectively following the first EDTA infusion (Arenas et al., 2019). 

Serum iron levels

An open-label trial (n=122) found that EDTA chelation therapy had a homeostatic effect on serum iron levels (Rudolph et al., 1991). Overall, iron levels decreased by 17.5%. However, in subjects with initial levels that were more than 30% above the mean, serum iron was decreased by 46.3% following 30 EDTA infusions. In subjects with initially low levels, serum iron was increased by 31.6% in men and 10.4% in women. 

Improved lipid profile

Several studies reported an improvement in lipid profiles following EDTA chelation therapy ( McDonagh et al., 1981; Maniscalco & Taylor, 2004; Olwin & Koppel, 1968;  McDonagh et al., 1982).

An open-label trial (n=221) reported an average decrease of 30 mg/dl in total cholesterol across all age groups studied following EDTA therapy ( McDonagh et al., 1981).

An open-label trial (n=100) that combined EDTA and antibiotic treatment found that lipid profiles improved significantly despite 86% of patients already being on continuous statin medication before the trial (Maniscalco & Taylor, 2004). 

A retrospective analysis (n=34) reported that improvements in the lipid profile were produced in most instances following the infusion of 12-15 g of EDTA. A reduction of 33% of total esterified fatty acids, 52% for triglycerides, 23% total cholesterol, 25% phospholipid phosphorus was measured ( Olwin & Koppel, 1968). 

An open-label trial (n=358) reported a statistically insignificant decline of 4% in the cholesterol/HDL ratio following EDTA. However, a more careful analysis of the data indicates that relatively low ratios tend to rise, high ratios tend to fall and those in a range of 4-4.9 tend to remain unchanged. This supports the idea of an "ideal" ratio and EDTAs ability to affect it (McDonagh et al., 1982).

A DB-RCT found no significant effect on the lipid profile of patients with PAD treated with EDTA (Guldager et al., 1993). 

Decreased serum urate

Two trials reported a benefit of decreasing serum urate through EDTA therapy (Lin et al., 2001; Lin et al., 2002). Lead chelation led to lower serum urate levels and higher urate clearances with no change in creatinine clearance or protein intake. 

Renal, urinary, reproductive systems

Improved renal function

As seen in the table below, several RCTs reported a slower rate of glomerular filtration rate (GFR) decline or improved renal function in CKD after receiving EDTA chelation therapy.

A retrospective analysis (n=3000) also reported improved renal function (Evers, 1979) as did an  open-label trial that reported a renal function increase of 12.8% after EDTA therapy that remained stable (10.2%) at 12 months (Lin et al., 2001). 

A study on cadmium-induced renal dysfunction found that EDTA only ameliorated the dysfunction if the initial urinary cadmium level was less than 10 µg/g (Wu et al., 2004). 

Creatinine/BUN levels

An open-label trial (n= 383) found that EDTA chelation therapy had a "homeostatic" effect on creatinine levels where low levels were raised, levels around the physiologically accepted value of 1.0 mg/dl were unchanged and high levels declined (McDonagh et al., 1982). A similar effect was found for BUN levels in a trial by the same authors (n=80) (McDonagh et al., 1982). 

Increased sexual potency

Several male patients reported improved sexual potency in a retrospective analysis (n=470) (Hancke & Flytlie, 1993).

Decreased prostatic obstruction, stone size and pelvic pain syndrome

An open-label trial (n=16) found that combined tetracycline and rectal EDTA reported that 4 patients experienced between 25-49% improvement and 8 patients experienced a greater than 50% improvement in their chronic prostatitis symptom index scores. Of 10 patients that additionally underwent transrectal ultrasound to measure prostatic stone size, it was found that the stones had decreased in size in 5 patients and completely resolved in 1 patient (Shoskes et al., 2005). A retrospective analysis (n=3000) also reported reduced prostatic obstruction by calculi (Evers, 1979). 

Respiratory system

Reduced symptoms of emphysema

A retrospective analysis (n=3000) reported reduced emphysema symptoms (Evers, 1979). 

Improved pulmonary function tests

An open-label trial (n=38) of patients with a chronic degenerative disease, of whom 26% had abnormal initial lung function tests reported improvements in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) tests following 30 EDTA infusions (Rudolph et al., 1989). After treatment, only 5% of subjects had abnormal FVC and even those subjects whose FVC remained abnormal showed improvements of 16.5%. The overall improvement for FVC was 12.1% and for FEV1 it was 12.8%.

Risk assessment 

Our analysis identified 21 risks that have appeared in human studies to date. All are short-term side effects of the infusion and over half came from the same case series and are not mentioned elsewhere. Many of the other risks are from early studies that applied high-dose protocols over a short period of time that are no longer in use. The TACT has firmly established the safety of EDTA chelation therapy as it is currently used. 

Table 4: Risk assessment  

Individual risks that have appeared in clinical trials

Hypocalcemia

Minor hypocalcemia was reported as an adverse event in the TACT (Lamas et al., 2013) in 6.2% of the chelation group and 3.5% of the placebo group. 

An open-label trial on the effect of EDTA on fasting serum calcium levels found that there was no significant change in long term serum calcium levels after 10, 20 or 30 infusions (McDonagh et al., 1983). A trend appeared towards a "homeostatic" effect on serum calcium where low levels rose, medium levels remained unchanged and high levels fell.

Because EDTA binds ionizable free calcium, rapid i.v. infusion may result in hypocalcemic tetany. Slow infusion (16.6 mg/min or less) generally only lowers the serum ionizable calcium ion concentration slightly. Clinically symptomatic hypocalcemia can be rapidly reversed with i.v. calcium gluconate (Rozema, 1997). 

Cardiac arrest

Severe hypocalcemia leading to cardiac arrest and death has also been reported (Baxter & Krenzelok, 2008; Brown et al., 2006), although these cases were due to medical errors in drug type, dose or rate of administration. 

A systematic review summarised all deaths after EDTA-chelation therapy reported since 1990 (Ernst, 2009). Nine fatalities were found but the quality of these reports was too poor to establish causality beyond doubt. The causes of death included myocardial infarction, cardiac arrest, arrhythmia, and others. 

With proper precautions, there should not be any fatalities since the LD50 of EDTA is 10-20 times greater than the doses in current use (Rozema, 1997).

Gastrointestinal symptoms

A case series reported that 5 patients came to the emergency department with GI symptoms that developed 30 min - 2 hours into chelation therapy at an outpatient clinic (Morgan et al., 2002). 

An early study that administered 5g EDTA per day for 5 days followed by a 2-day break reported that mild GI symptoms including nausea, diarrhea, and epigastric pain were common (Clarke et al., 1956). 

An open-label trial mentioned that symptoms such as nausea, vomiting and dry mouth were encountered when the infusion rate was too rapid (Casdorph, 1981). 

It is hypothesized that suppressed intestinal villi turnover due to zinc depletion or hypocalcemia might be the cause of gastrointestinal symptoms (Rozema, 1997). 

Fever

Two studies reported a febrile reaction following EDTA chelation therapy (Morgan et al., 2002; Perry & Schroeder, 1958). A case series reported that 5 patients came to the emergency department with a fever that developed 30 min - 2 hours into chelation therapy at an outpatient clinic (Morgan et al., 2002). Fever following EDTA infusion was also reported as a rare complication in an early case series that used high, daily doses of EDTA (Perry & Schroeder, 1958). 

Increased creatinine/nephrotoxicity

An early study reported that doses higher than 3 g EDTA caused renal irritation in some patients with urinary findings of albuminuria and hyaline casts ( Seven, 1958 ).

A case series reported that 3 patients came to the emergency department with an increased serum creatinine that developed 30 min - 2 hours into chelation therapy at an outpatient clinic (Morgan et al., 2002). 

Renal tubular vacuolization and hydropic degeneration were seen in the autopsy of patients that had received one or more large doses (6-13.5 g over 60 minutes) of EDTA for hypercalcemia ( Holland et al., 1953 ). These doses are substantially higher than the doses used today. 

One open-label study found that fasting serum creatinine decreased with EDTA chelation therapy and concluded EDTA is not nephrotoxic, and that it may improve kidney function (McDonagh et al., 1982). This is supported by the studies in the benefits section that found kidney function was improved following a series of EDTA infusions.

In cases where the dose, rate or frequency of treatment is too high, nephrotoxicity may occur. It is reversible though it may take several days to resolve (Rozema, 1997). Renal function should be carefully assessed prior to initiating treatment with EDTA and regular urinalysis should be performed during treatment. The dose should be adjusted based on creatinine clearance and serum creatinine levels. If a normal baseline creatinine level rises during therapy, infusions should be temporarily stopped (2-4 weeks) until it normalizes and the dose should be adjusted accordingly (Rozema, 1997). 

Burning/pain/thrombophlebitis at the injection site

Since EDTA is an amino acid it may produce local pain when administered intravenously. Two studies reported burning/pain at the injection site (Clarke et al., 1956; Casdorph, 1981) that could be largely prevented by slowing the rate of infusion. 

The use of magnesium and bicarbonate both reduce discomfort at the treatment site and may even eliminate the need for a local anesthetic (Rozema, 1997).

The risk of superficial thrombophlebitis can be reduced by adding 1000-5000 units of heparin to the infusion (Rozema, 1997). 

Numbness around mouth, giddiness, and drowsiness

One study reported n umbness around the mouth, giddiness, and drowsiness following EDTA infusion (Clarke et al., 1956). 

Bone loss

A clinical trial found that serum calcium and phosphate decreased and PTH increased (2.5x) following treatment with EDTA therapy ( Guldager et al., 1993 ). This, combined with the finding that there were no increased signs of osteoblastic activity to indicate remodelling led the authors to conclude that EDTA therapy is accompanied by bone loss.

The rise in PTH may stimulate osteoclastic activity for approximately 21 days. It also then stimulates osteoblastic activity that increases bone formation for 120 days and should improve bone density ( Rozema, 1997). An  open-label trial that actually measured bone density before and after 30 EDTA infusions found no significant change in the group overall but that there was a 2% increase in bone density in participants with preexisting osteoporosis (Rudolph et al., 1988).

Decreased effect of warfarin

One study reported impaired warfarin anticoagulation in a patient undergoing chelation therapy (Grebe & Gregory, 2002). The international normalized ratio (INR) fell from 2.6 to 1.6 the day after therapy was administered. The effect of EDTA chelation on anticoagulation is uncertain but as a potential interaction, clinicians should consider INR monitoring in patients undergoing chelation therapy. 

Hypoglycemia

Blood glucose may fall during or after an infusion of EDTA because EDTA binds zinc and calcium. Zinc is required for the renal tubular reabsorption of glucose and hypoglycemia may be a response to hypocalcemia (Rozema, 1997). Hypoglycemia was not specifically reported in any of the trials we analyzed although "faintness" was. 

Hypoglycemia can generally be avoided with adequate caloric intake before and during treatments. All patients should be informed about the possibility of hypoglycemia during or after the infusion and be instructed to eat a meal before treatment and to bring a snack to the treatment. A 50% glucose solution for i.v. administration should be readily available in the infusion area (Rozema, 1997). 

Mucocutaneous lesions

Mucocutaneous lesions resembling acute avitaminosis of B vitamins developed in two patients following daily infusions of calcium disodium ethylene diamine tetraacetic acid (CaNa2EDTA) (Perry & Schroeder, 1958). They resolved rapidly over a few days with vitamin B supplementation (Perry & Schroeder, 1958).

Other risks

A case series (n=5) reported that patients came to the emergency department with a variety of symptoms that developed 30 min - 2 hours into chelation therapy at an outpatient clinic (Morgan et al., 2002): 

Theoretical risks

EDTA has been shown to cause birth defects in animals, although this was partially reversible with zinc supplementation (Rozema, 1997). The reactivation of tuberculosis within calcified foci is a theoretical risk so patients with known Ghon's complex should be monitored (Rozema, 1997). The embolization of plaque is another purely theoretical risk that has not been seen in trials or clinical practice to date (Rozema, 1997). 

Mechanism of action 

Type

EDTA refers to two different drugs with different approved uses. Na2EDTA is indicated for the emergency treatment of hypercalcemia and digoxin toxicity with ventricular arrhythmias. CaNa2EDTA is approved for the treatment of lead poisoning and lead encephalopathy. Most trials included in our analysis used Na2EDTA. CaNa2EDTA does not possess all the mechanisms of action that Na2EDTA does to reduce or prevent vascular disease (Chappell & Drisko, 2014). It does, however, increase NO production and decrease free radical activity. We were unable to identify any published studies that used CaNa2EDTA as a treatment for cardiovascular disease. 

Mechanism of action

Several possible mechanisms for EDTA's effectiveness in preventing/reversing cardiovascular disease have been proposed.

The "roto-rooter" hypothesis claims that plaque structure depends on the calcium within it and through its removal, plaques can be disintegrated, leading to widened arteries and increased blood flow (Clarke et al., 1956). Criticism has been levelled against this hypothesis because of outdated concepts on the pathophysiology of atherosclerosis and inability of EDTA (water-soluble) to effectively complex with plaque calcium as plaques are an integral part of the cell membrane (Lewin, 1997). However, removal of metastatic calcium has been demonstrated in rabbit aortas (Kaman et al., 1990) and EDTA mobilized 30-fold more calcium from atherosclerotic plaque than physiologic saline did in human cadavers (Wilder et al., 1962). Theoretically, 3 g of EDTA would only remove 324 mg of calcium (double the normal daily amount) and cannot account for all the clinical effects witnessed (Rozema, 1997).

A second theory relies on PTH and suggests that chelation of ionized calcium can stimulate the secretion of PTH. This promotes bone mineralization by calcium mobilized from plaques which may lead to softening of the arteries and destruction of plaques (Rudolph et al., 1988; Grier & Meyer, 1993). 

A third (and currently the most popular) theory is the chelation of toxic heavy metals. EDTA is not readily taken up by cells and its effects are likely due to the chelation of extracellular metals, which leads to a decrease in intracellular metals. Many supplements/medications (curcumin, ACEi, angiotensin II receptor blockers (ARB) and metformin) that influence CVD outcomes have multidentate structures that can function as chelating agents. For example, curcumin has been shown to chelate iron, lead and cadmium (Ouyang et al., 2015). It is possible that ACEi and ARB are able to inhibit the formation of advanced glycation end products by chelation of transition metals such as copper (Ouyang et al., 2015). 

There is robust epidemiological evidence linking heavy metal levels at the upper limit of what is considered safe to hypertension, atherosclerosis, dyslipidemia, CAD, and PAD (Peguero et al., 2014).  High blood lead levels have been associated with a 55% increased risk of cardiovascular mortality and a 2-fold higher risk of mortality from stroke. High bone lead levels have also been associated with a 2.64 times increased risk of cardiovascular disease ( Mathew et al., 2017 ).

Elevated levels of urinary cadmium are also correlated with the incidence of cardiovascular mortality (Peguero et al., 2014), PAD (nearly two times the risk), hypertension, and metabolic syndrome (Mathew et al., 2017). Additionally,  chronic low-level cadmium exposure has been associated with macrophage dysfunction indicating a possible relation to the creation of foam cells found in atherosclerotic plaques (Mathew et al., 2017).  Lead and cadmium may cause epigenetic changes like DNA methylation and alteration of gene expression that is linked to vascular calcification and severity of CVD ( Sultan et al., 2017 ).

Other theories include a free radical scavenging action (Gutteridge,1987), a reduction of total body iron stores (Rudolph et al.,1991), beneficial effects on lipids ( Lamb & Leake, 1992 ; Steinberg et al., 1989 ),  cell membrane stabilization, arterial dilatation due to calcium channel blocking action, improvement of arterial wall elasticity and increased production of nitric oxide (Knudtson et al., 2002).  Another possible mechanism is decreased platelet aggregation, either by irreversibly altering the platelet calcium ratio or by altering a pathway that requires increased calcium (Frishman, 2001). 

Route

Human and rat studies reported that CaNa2EDTA and Na2EDTA are poorly absorbed via oral routes (5%) of administration (Safety assessment EDTA, 2002). I.v. infusions and intramuscular injections of EDTA are excreted entirely through the kidneys (Safety assessment EDTA, 2002  ) whereas, orally administered EDTA is mostly eliminated through the feces (at least in rats). Taken orally, 95% of the EDTA remains in the digestive tract where it binds to minerals and trace elements from food, blocking their absorption. Over a longer time period, this could potentially lead to nutritional deficiencies (Cranton, 2001; Rozema, 1997). Studies of pre and post-treatment body mineral content during continuous oral EDTA treatment are needed before the safety of oral preparations can be established.

Intramuscular injection of Na2EDTA is contraindicated as it may cause tissue sloughing and marked pain at the site of administration (Rozema, 1997). 

There is also evidence that the colon absorbs very little EDTA (Cranton, 2001). Administration by enema resulted in only a 7% recovery in the urine over the next 6 hours compared to an 85% recovery of i.v. EDTA. Additionally, a study in dogs showed that half of the dogs developed mucosal hemorrhages from the EDTA solution (Cranton, 2001). A suppository would release its content in a very small area and could lead to inhibition of important defences against cancer in the long term such as SOD. Long term studies are lacking to establish the safety of rectal EDTA.

EDTA i.v. infusions have been used extensively and their safety is well-established, particularly in light of the results of the TACT.

Dose & Toxicity

Doses of EDTA used in the analyzed studies ranged from 0.5 g up to 5 g but the majority used 3 g. Most studies added other components to the infusate (see Table 2). The best evidence for dosing comes from the TACT which used the published protocol followed by several groups in the chelation community. The infusate consisted of:

Two meta-analyses of observational data showed that although most studies used 3 g EDTA, those that used 1.5 g were equally effective (Chappell & Stahl, 1993; Chappell et al., 1994). A retrospective study comparing patients with PAD treated with a 3g dose of EDTA to those treated with a 1.5 g dose found those treated with the lower dose improved using Doppler ultrasound by an average of 123% while the patients in the 3g group improved by an average of 70% ( Chappell & Drisko, 2014). The German Chelation Society approves both a 2 and 3 g dose (Chappell & Drisko, 2014). Dose recommendations by other experts include 3 g normally and up to 5 g for large patients (50 mg/kg) ( Cranton, 2001 ), 1.5 or 3 g ( Rozema, 1997; Van der Schaar, 2012). 

Rate

Rapid i.v. infusion of Na2EDTA may result in hypocalcemia because of the relatively high concentration of ionizable free calcium binding to the EDTA. Slow infusion (16.6 mg/min or less) generally doesn't result in hypocalcemia (Rozema, 1997). 

All current protocols insist on an infusion rate of disodium EDTA not faster than 1 g per hour to avoid overloading the kidneys (Chappell & Drisko, 2014) meaning a 3 g dose is infused over at least 3 hours.

Frequency

The frequency of infusions ranged from daily to monthly in the trials we analyzed. The TACT trial performed 30 weekly sessions followed by 10 sessions 2-8 weeks apart. Sessions must be at least 24 hours apart (Rozema, 1997). 

Nutritional supplementation

Trace element status should be assessed before commencing EDTA therapy by obtaining a careful dietary history and by testing urine, and/or hair, and/or blood. Urine measurements of a spectrum of metallic elements are recommended to screen for an excess of toxic elements and deficiency or excess of trace elements.

In order to prevent a potential vitamin and mineral depletion, nutritional supplementation was provided in several of the studies (see Vascular Rejuvenation using EDTA#Table 2). A daily low-dose vitamin regimen consisting of vitamin B6 25 mg, zinc 25 mg, copper 2 mg, manganese 15 mg, and chromium 50 mcg was administered to all patients during the treatment period of the TACT. 

Toxicity

In all available toxicology studies (rodent and nonrodent species), the lowest dose of both CaNa2EDTA and Na2EDTA that caused toxicological effects was 750 mg/kg/day ( Safety assessment EDTA, 2002 ). 

Section 5: Presentation of Results 

The following "tornado" diagram summarizes the results of the previous sections:

• The risk-benefit criteria are listed in the category column.

• The weighted score after factoring in uncertainty is shown as a numerical value.

• The weight of the criteria is proportional to the width of the columns. 

• Risk and benefit criteria are assigned to either low (1-1.66), medium (1.67-2.33), or high (2.34-3) weighted categories based on the results of the assessment in Table 5 and Table 6.

• The diagram is filterable by category so the main risks and benefits for each system can be viewed. 
  

To view the tornado diagram as a pdf please click on the thumbnail below:

Open

For those who would prefer to view the  document  in excel, we have included  the original .xls file.

EDTA RBA v1.3.xlsx

Section 6: Conclusions 

The extremely positive results from over 100 observational studies combined with the more recent findings of the TACT trial provide substantial evidence on the effectiveness and safety of EDTA chelation therapy in cardiovascular disease. 

The negative attitude in conventional medicine towards EDTA chelation therapy for cardiovascular disease was based on conclusions from a few poorly conducted trials which in total, enrolled fewer than 300 subjects (compared to more than 20,000 subjects in the observational studies) and is gradually changing.

The results of the TACT trial have restimulated the conventional medical community's interest in EDTA chelation therapy and the American Heart Association and the American College of Cardiology revised their guidelines and upgraded EDTA chelation therapy for the treatment of ischemic heart disease from IIIC (not recommended) to IIB (may be considered) (Fihn et al., 2014; Fihn et al., 2012). This places EDTA in the same category, for example, as treatment with aspirin (75 to 162 mg daily) and clopidogrel (75 mg daily) in certain high-risk patients with stable ischemic heart disease. 

Based on the high level of evidence, EDTA chelation therapy should be recommended as a treatment option in case of overt CVD (including the presence of arterial plaques, calcification, alterations in blood flow, or diagnosed cardiovascular conditions).

Additionally, while no direct evidence yet exists for EDTA chelation therapy in the primary prevention of vascular disease its use could still be considered due to the minimal risks and potentially substantial benefits. Given that currently, the most widely accepted hypothesis for EDTA's effectiveness in CVD is the removal of heavy metals, a urine challenge test could be used to determine whether EDTA chelation therapy should be performed for primary prevention. 

Main benefits

The main benefits seen in clinical trials of EDTA chelation therapy for CVD are:

• decreased cardiovascular adverse events (mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina)

• decreased clinical symptoms of angina

• decreased clinical symptoms of peripheral arterial disease

• decreased arterial stenosis

• decreased lead levels

• improved kidney function 

Main risks

The main risks that have appeared in clinical trials were minor. The majority are related to overdose or too rapid infusion and as such, can be easily mitigated. They include:

• hypocalcemia 

• nephrotoxicity

• local thrombophlebitis 

• hypotension

• hypoglycemia 

• depletion of essential minerals 

Risk Mitigation Strategies

• use a slow rate of infusion

• maximum of 50 mg/kg/dose 

• eat before and during treatment to avoid hypoglycemia and ensure a glucose infusion is readily available

• monitor for clinical signs of hypocalcemia and make sure vials of injectable calcium gluconate are readily available

• assess trace mineral status before commencing therapy 

• replenish essential minerals

• monitor kidney function

• a "crash cart" type of emergency kit should be readily accessible in the treatment area containing the usual medical supplies and equipment needed for cardiopulmonary resuscitation

Contraindications

• allergy to EDTA (rare) or other components of the infusion (local anesthetic, thiamine)

• renal impairment (low-dose if creatinine >2.8 mg/dl)

• severe liver disease 

• pregnancy - teratogenic in animals in the absence of adequate zinc (Chappell & Janson, 1996)

• congestive heart failure (volume overload)

• acute lead encephalopathy (>80 µg/dl) (Rozema, 1997)

Section 7: Practical Application 

Suggested Treatment Protocol

• Follow the risk mitigation strategies and be aware of the general contraindications

• Choose a qualified physician

• The determination of whether to use EDTA as primary prevention (no identified signs of CVD disease) should be made based on the results of an EDTA urine challenge test

• Before beginning therapy, assess trace mineral status and kidney function

• The highest level of evidence for a safe and effective protocol comes from the TACT

• The protocol they used is followed by organizations such as the American College for Advancement in Medicine, the International College of Integrative Medicine, the American Board of Clinical Metal Toxicology, and the International Board of Clinical Metal Toxicology

  • The infusate consisted of 3 grams disodium EDTA, adjusted downward based on estimated glomerular filtration rate, 7 grams of ascorbic acid, 2 grams of magnesium chloride, 100 mg of procaine HCl, 2500 U of unfractionated heparin, 2 mEq potassium chloride, 840 mg sodium bicarbonate, 250 mg pantothenic acid, 100 mg thiamine, 100 mg pyridoxine, and sterile water to make up 500 mL of solution

  • 40 infusions - 30 (once per week) + 10 (2-8 weeks apart) 

  • A daily low-dose vitamin regimen consisting of vitamin B6 25 mg, zinc 25 mg, copper 2 mg, manganese 15 mg, and chromium 50 mcg during the treatment period to avoid mineral depletion

• The full benefits may not be visible for up to 3 months after a series of infusions have been completed.

• Depending on patient response, follow-up treatments may be given once or twice monthly for long term maintenance, to sustain improvement and to prevent recurrence of symptoms.

• For a detailed description see Rozema's protocol