Chelation Therapy in Cardiovascular Disease: An Update on the Science


By Joel Kahn, MD, FACC

The current practice of traditional cardiovascular medicine is to address common factors like smoking, blood pressure, diabetes, metabolic syndrome, and dyslipidemias. In some clinics, additional time will be spent on diet, fitness, stress, sleep, and oral health. Even less commonly, a search for root causes like genetics, detoxification pathways, epigenetics, chronic infections, and allergies will be considered. The usual focus is on pharmacology and reducing future major events like heart attacks, strokes, and death with prescription drugs.

The concepts of halting and even reversing atherosclerosis is rarely mentioned in cardiac visits. Yet, both randomized and observational studies have demonstrated that atherosclerosis is amenable to reversal with a focus on lifestyle such as the Ornish Lifestyle Heart Trial.1

One possible overlooked cause of cardiovascular disease (CVD) is biotoxicity with heavy metals. A recent review article focused on the role of the massive increases in human exposure to heavy metals. Mercury, lead, chromium, cadmium, and arsenic have been the most common heavy metals that induce human poisonings and disease. The authors identified the basis for acute or chronic poisonings following exposure through water, air, and food.

Bioaccumulation of these heavy metals leads to a diversity of toxic effects on a variety of body tissues and organs. Heavy metals disrupt cellular events, including growth, proliferation, differentiation, damage-repairing processes, and apoptosis. Comparison of the mechanisms of action reveals similar pathways for these metals to induce toxicity, including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress.

Some toxic metals, including chromium, cadmium, and arsenic cause genomic instability. Defects in DNA repair following the induction of oxidative stress and DNA damage by these three metals have been considered as the cause of their carcinogenicity.2

While the idea that “heavy metal” accumulation may contribute to CVD may seem obvious to integrative practitioners, it is still novel to cardiology specialists. One of the most compelling recent studies looked at the role of lead and mortality in the USA and was completed and published recently. Over 14,000 subjects had levels of lead measured in their blood between 1994-1998 and were followed up through 2011.

During a median follow-up of 19 years, over 4,400 people died with 38% from CVD and 22% specifically from ischemic heart disease. An increasing concentration of lead in blood was associated with all-cause mortality, CVD mortality, and ischemic heart mortality. The proportion of all deaths attributable to lead was 18% but rose to 29% for CVD mortality and 37% of ischemic heart deaths. The authors concluded that over 400,000 deaths in the USA alone annually may be related to lead toxicity and is a risk factor for CVD.3

While elevated blood lead levels are associated with higher rates of death in population studies, can heavy metals accumulate in cardiac tissue of patients with diseases like dilated cardiomyopathy? One of the most impressive studies was published over 20 years ago but it remains relevant. The researchers sought to investigate the possible pathogenetic role of myocardial trace elements (TE) in patients with various forms of cardiac failure. Researchers performed myocardial biopsy on 13 patients with dilated cardiomyopathy and measured 32 trace elements, including mercury. The results of the biopsies were compared to biopsy and surgical samples of 25 patients with valvular and ischemic heart disease and four normal subjects.

A >10,000 times increase for mercury and antimony concentration was measured in myocardial samples in patients with dilated cardiomyopathy. In patients with dilated cardiomyopathy, mean mercury concentrations were 22,000 times higher than control subjects. The investigators concluded that a large increase of myocardial toxins was present in patients with dilated cardiomyopathy and may adversely affect mitochondrial activity and worsen cellular function.4

The idea that components of plaque might be bound and removed by chemical agents to reduce the overall burden of atherosclerosis and subsequent events is not considered by most cardiac clinicians. Yet, there is scientific evidence that indicates that this may be possible. While gene editing and new pharmacological agents may be available in the future, such as medications that lower lipoprotein(a) cholesterol, for now, chelation therapy is the most hopeful approach to plaque reversal.

Chelation means “to grab” or “to bind.” Chelation, in the context of medical therapeutics, is a process in which the organic chelator molecules are introduced into the blood, where they bind the target metal ions with high affinity. Edetate disodium (EDTA), a synthetic chelating agent first synthesized in Germany in the 1930s, has up to 6 binding sites with which to hold and envelop metal ions.

When a chelating agent like EDTA is injected into the veins, or, perhaps, administered orally or rectally, it “grabs” heavy metals and minerals such as lead, mercury, copper, iron, arsenic, aluminum, and calcium and removes them from the body. For over 60 years, chelation therapy has been used in patients with cardiovascular disease (CVD) and consideration of its role is timely. This discussion will be limited to EDTA as it is the most common chelating agent by far used in studies of CVD.

It is assumed that chelating agents remove heavy metals stored in the body. A recent study looked at the ability of EDTA to reduce lead measured by provocative urinary testing, which is considered a marker for total body lead stores. The study population was 15 healthy, asymptomatic patients who were evaluated for accumulated total body lead stores as part of a routine health screening.

After establishing their baseline stored lead levels, patients received a series of intravenous chelation infusions to reduce body lead. The average number of infusions given was 14, over an average period of 24 months. After the series of chelations, there was an average reduction in lead excreted in the urine of 39%.  All 15 subjects had a reduction in the amount of excreted lead after the series of chelation infusions. The researchers concluded that monthly (or less often) infusions of calcium EDTA along with other vitamins can reduce total body lead levels.5

I practice in Michigan and there is a Michigan connection to the introduction of EDTA chelation for the treatment of CVD. Norman E. Clarke Sr., MD, was a renowned cardiologist and chief of research at the Providence Hospital now in Southfield, Michigan. Dr Clarke theorized that because EDTA binds calcium, it might eliminate calcium deposits from inside blood vessels. Dr. Clarke and his colleagues were the first to test this hypothesis through clinical studies on patients with CVD.

The medical utility of edetate disodium was discovered after some trial and error. After World War II, the US Navy discovered that EDTA was effective in treating lead poisoning in naval shipyard workers using lead-based paint. Impressive recoveries in patients with CVD were reported by Dr Clarke. He continued to be an avid proponent of chelation therapy and was largely responsible for generating scientific interest and keeping it alive during the first 20 years of its use. Dr. Clarke lived to be 92 years of age with a sharp mind and sustained interest in chelation therapy.

Other doctors, realizing the merits of chelation therapy, had begun extensive clinical treatment programs in private hospitals. One such physician was H. Ray Evers, MD. Dr. Evers observed that “from our experience in treating patients with varying degrees of calcinosis (arteriosclerosis, atherosclerosis, etc.), we will unequivocally state that it is our opinion that every patient with this disease in any part of the body should be given a therapeutic trial before any type of vascular surgery is performed.”

Dr. Evers also noted: “We find in all cases of angina, characterized by the patient having no need for vasodilators after about the fifth infusion, and that ninety-one percent of these problems in the lower extremities make significant gains, including regaining ability to walk long distances comfortably, freedom from claudication, and evidence of improved distal circulation.” Although the testimonial was strong, Dr. Evers was investigated by several state boards and lost his medical license before his death. Overall, credible science was needed if EDTA chelation was to ever to rise to an accepted therapeutic option.6,7

Maniscalco and Taylor reported in 2004 that a combination of rectal EDTA, oral tetracycline, and vitamins had a beneficial impact on CVD measured by coronary calcium CT scoring. One hundred patients with stable coronary disease and positive calcium CT scores were enrolled into a four-month study. The CT scoring was repeated at four months. Seventy-seven patients completed the study. Overall, 44 responded with significant decreases in total CT calcium scores, the average decrease being 14%. Angina was decreased or completely prevented in 16 of 19 symptomatic patients. Lipid profiles improved significantly. Overall, patients tolerated the therapy quite well.8

The early practitioners of chelation therapy got a tremendous boost in 1999 when a cardiologist at the Mt. Sinai Medical Center in Miami, Florida, Gervasio Lamas, MD, listened to a patient’s testimonial about an experience with chelation. He learned that most patients getting EDTA chelation also received high-dose multivitamins, including vitamin C. After researching the field, he prepared, submitted, and was awarded a grant of over $30 million from the National Institutes of Health that agreed to fund the “definitive trial” for chelation therapy. This trial was called the Trial to Assess Chelation Therapy (TACT).

The trial was designed to be a randomized, double-blind, placebo-controlled, 2×2 factorial clinical trial, testing the benefits and risks of 40 infusions of a multicomponent disodium EDTA chelation solution compared with placebo and an oral, high-dose multivitamin and mineral supplement.

Beginning in 2002, TACT randomized 1,708 patients with a prior heart attack for an average of approximately four years. A factorial design was selected for TACT, in which eligible patients were randomly assigned to one of four groups:

  1. Active intravenous (IV) chelation infusions + active oral multivitamins and minerals (OMVM)
  2. Active IV chelation infusions + placebo OMVM
  3. Placebo IV chelation infusions + active OMVM
  4. Placebo IV chelation infusions + placebo OMVM

The primary end point was a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900-patient sub-study examined quality-of-life outcomes. Enrollment began in September 2003 and was completed in October 2010. No cardiac imaging or calcium CT scoring was done by protocol during the study.9

These results showed that for the group overall, chelation therapy modestly reduced the risk of adverse cardiovascular outcomes; but though the study provided a platform for further research, researchers cautioned that the study wasn’t conclusive enough to support routine use of EDTA chelation after a heart attack.10

Since the completion of the TACT trial, a number of additional papers have been published. Taken together, this research indicated:

  • C therapy modestly reduced bad outcomes (hospitalization for chest pain, stroke, heart attack, and need for a stent) compared to the placebo group.
  • In patients with a prior heart attack and diabetes, chelation therapy reduced bad outcomes in the five years of follow-up by nearly 40%.
  • In patients with a large anterior heart attack before chelation therapy, the treatment also reduced bad outcomes in follow-up by nearly 40%.
  • When chelation therapy was combined with high dose oral multivitamins, even more benefit was obtained with chelation therapy.
  • Adverse effects from chelation therapy were infrequent.

Most of the benefit in the TACT trial was seen in patients with prior myocardial infarction and diabetes. These patients were analyzed separately.

A total of 633 (37%) patients had diabetes mellitus (322 EDTA and 311 placebo). EDTA reduced the primary end point (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina; 25% versus 38%; P<0.001) over five years. All-cause mortality was reduced by EDTA chelation (10% versus 16%; P=0.011), as was the secondary end point (cardiovascular death, reinfarction, or stroke; 11% versus 17%; P=0.017). The number needed to treat to reduce one primary end point over five years was 6.5. There was no reduction in events in non–diabetes mellitus (n=1075; P=0.877).10

The TACT investigators determined if the type of therapy for diabetes influenced outcomes in the study. There were 162 (26%) patients treated with insulin; 301 (48%) with oral hypoglycemics only; and 170 (27%) receiving no pharmacologic treatment for diabetes. Patients on insulin reached the primary endpoint more frequently than patients on no pharmacologic treatment [61 (38%) vs 49 (29%) [p = 0.022)] or oral hypoglycemics [61 (38%) vs 87 (29%) [p = 0.024)].

The investigators concluded that chelation treatment in stable, post-myocardial infarction patients with diabetes requiring insulin therapy (versus other diabetic therapies) may realize the greatest benefit from EDTA chelation as they are at the greatest overall risk for events.11 

Another analysis of the TACT results focused on the location of the prior MI in patients enrolled. Among patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (p = 0.003) among anterior MI patients, but not in post non-anterior MI. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables. Researchers concluded that EDTA reduced the risk of cardiovascular events among patients with a prior anterior MI.12

In a substudy of the TACT study, 911 patients were assessed with quality of life (QOL) measures. In the 451 patients randomized to chelation and in the 460 patients randomized to placebo there was no evidence for a treatment-related differences. There was no statistically significant evidence of a treatment-related difference in the Mental Health Inventory-5. None of the secondary QOL measures showed a consistent treatment-related difference.13

While the TACT trial focused on CVD, there exists a challenging problem dealing with peripheral arterial disease (PAD). The most advanced cases of PAD involve severe limb disease, including critical limb ischemia (CLI). This is usually due to an infra-popliteal disease with foot pain and ischemic ulcerations, including gangrene. The risk of amputation is very high.

The TACT study group organized a separate unblinded pilot study in 10 diabetic patients to determine whether there was a signal of benefit for EDTA infusions in patients with CLI. Each patient received up to 50 edetate disodium-based infusions and was assessed for safety, clinical efficacy, metal excretion, and quality of life. The primary endpoint was to assess the effect of edetate disodium-based therapy plus vitamins in patients with diabetes and infra-popliteal peripheral artery disease presenting with severe CLI and determine if there were improvements in vascular flow parameters.

There were no major adverse cardiovascular events during the infusion phase through the one-year follow-up. Patients completing 40 infusions demonstrated complete wound healing and improvement in the quality of life. This small study produced impressive case studies and demonstrated a potential signal of benefit and preliminary evidence of safety. Based on these findings, a randomized study (TACT3a) was designed and is underway.14

In view of increasing interest in chelation therapy for CVD, the Cochrane Database reviewed data through 2019. They included five studies with a total of 1993 randomized participants, the bulk of which were from the TACT study. Three studies enrolled participants with peripheral vascular disease and two studies included participants with coronary artery disease, one of which specifically recruited people who had had a myocardial infarction. Overall, the reviewers concluded that there was no evidence of major or minor adverse events associated with EDTA chelation treatment. Furthermore, they determined that there was insufficient evidence to determine the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of people with atherosclerotic cardiovascular disease. They called for more high-quality, randomized controlled trials that assess the effects of chelation therapy on longevity and quality of life among people with atherosclerotic CVD.15

With the goal of reproducing the results of TACT, the investigators designed and got funding for TACT2, exclusively in diabetic patients with a prior MI. Again, there is a 2 × 2 factorial design for TACT2, randomly assigning patients to 40 infusions of the TACT chelation solution versus placebo infusions, and high doses of OMVM versus oral placebo. TACT2 will also collect blood and urine throughout the infusion period and will relate baseline lead and cadmium levels to risk of future events. In addition, analyses will be performed to determine whether reduction in lead and cadmium levels are causally associated with reduced cardiovascular risk. over the coming months. At present, TACT2 is enrolling and following patients.16,17

Recently, the impact of EDTA chelation was assessed in workers exposed to high levels of lead. The investigators aimed to compare the basal and arrhythmogenic ECG parameters of lead-exposed workers before and after chelation therapy and to evaluate the effect of acute change of blood lead levels on ECG. Forty consecutive, occupationally lead-exposed workers were enrolled; demographic, blood, echocardiographic, and electrocardiographic data were analyzed before and after chelation therapy. Pmax, P min, P Wave Dispersion, and QT Dispersion values, which are arrhythmia predictors, were significantly lower after chelation therapy compared to values before chelation therapy. The researchers concluded that lead-exposed workers are under the risk of ventricular and atrial arrythmias and chelation treatment has a positive effect on these parameters.18

Clearly, EDTA chelation is a hopeful therapy for CVD. Despite interest and practice for over 60 years, the scientific literature is optimistic but not adequate so far to have influenced the practice of conventional cardiology. With rare exception, you will not find chelation centers at clinics or hospitals. Perhaps TACT2 and TACT3a will provide findings that provide results to move the needle towards wider acceptance of the benefits of EDTA chelation.

Still unknown is whether chelation works by reducing the burden of toxic heavy metals, reducing plaque burden, or both. The current view of preventive cardiovascular specialists is to replace non-calcified and high-risk plaque with calcified and lower risk deposits using statins and other lipid active agents. Therefore, considerable basic science and clinical trials will likely be necessary before there is widespread implementation of EDTA chelation therapy in CVD.

This article was originally published in Townsend Letter, December 2021.


References

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  3. Lanphear BP, et al. Low-level lead exposure and mortality in US adults. Lancet. 2018;3(4)e177-184.
  4. Frustaci A, et al. Marked elevation of myocardial trace elements in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1999;33(6) 1578-1583.
  5. Petteruti S. Reduction of lead levels in patients following a long-term intermittent EDTA-based intravenous chelation infusions. Cureus. 2020;24(12)E11685.
  6. https://edta.net/the-early-history-of-edta-chelation
  7. Clarke NE, et al. Treatment of angina pectoris with EDT. Am J Med Sci. 1956;232(6) 654-6.
  8. Maniscalco BS, et al. Calcification in coronary artery disease can be reversed by EDTA-tertracycline long-term chemotherapy. Pathophysiology. 2004;11(2)95-101.
  9. Lamas GA, et al. Design of the Trial to Assess Chelaton Therapy (TACT). Am Heart J. 2012;163(1)7-12.
  10. E, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circulation. 2014;7:15-24.
  11. Escolar E, et al. Possible differential benefits EDTA in post-myocardial infarction patients with diabetes treated with different hypoglycemic strategies in the TACT. J Diabetes Complications. 2020;34(8):107616.
  12. Lewis EF, et al. Differential outcomes with EDTA treatment among stable post anterior vs non-anterior myocardial infarction patients. Cardiovasc Revasc Med. 2020;21(11)1389-1395.
  13. Mark DB, et al. Quality-of-life outcomes with a EDTA chelation regimen for coronary disease: results from the TACT randomized trial. Circ Cardiovasc Qual Outcomes. 2014;7(4)508-516.
  14. Arenas I, et al. Limb preservation using EDTA based chelation in patients with diabetes and critical limb ischemia:An open-label pilot study. Cureus. 2019;11(12)e6477.
  15. Villaruz-Sulit, MV et al. Chelation therapy for atherosclerotic cardiovascular disease. 2020. Cochrane Database Syst Rev;5(5):CD002785.
  16. Lamas GA, et al. Heavy metals, cardiovascular disease, and the unexpected benefits of chelation therapy. J Am Coll Cardiol. 2016;67(20)2411-2418.
  17. https://tact2.org/
  18. Karanfil M, et al. Effect of chelation therapy on arrhythmogenic and basal ECG parameters of lead exposed workers. Arch Environ Occup Health. 2021;April 10-1-7.


About the Author

Joel Kahn, MD, FACC, is an integrative cardiologist. He is the founder of Kahn Center for Cardiac Longevity and is a clinical professor of medicine at Wayne State University School of Medicine.