Questions and Answers: The NIH Trials of EDTA Chelation Therapy for Coronary Heart Disease

The National Institutes of Health (NIH) has sponsored two trials of an EDTA (edetate) chelation therapy regimen for coronary heart disease (CHD).

• The first study, called the Trial to Assess Chelation Therapy (TACT), has been completed. Its principal results and the results in patients with diabetes have been published.
• The second study, Trial to Assess Chelation Therapy 2 (TACT2), has also been completed. Its principal results have been published.

The questions and answers below provide information on both studies, as well as background information on chelation therapy and on CHD in general.

About the First Study

What was the Trial to Assess Chelation Therapy (TACT)?

TACT was the first large-scale, multicenter study designed to determine the safety and efficacy of EDTA chelation therapy (specifically disodium EDTA) for individuals with prior heart attacks. NIH’s National Heart, Lung, and Blood Institute (NHLBI) and National Center for Complementary and Integrative Health (NCCIH) cosponsored TACT. This study was more than 20 times larger than any previous randomized controlled trial of chelation therapy for CHD. It was designed to be large enough to detect if there are any moderate benefits associated with the therapy.

Why did NCCIH and NHLBI decide to study this therapy?

In addition to effective standard therapies, such as lifestyle modifications, medications, and surgical procedures, some patients with CHD seek out EDTA chelation therapy as a treatment option. Prior to TACT, the evidence cited in support of using EDTA chelation therapy was in the form of case reports.

Therefore, NCCIH and NHLBI saw a public health need to conduct a large-scale, well-designed clinical trial that could determine (1) whether EDTA chelation therapy is safe and might be effective for treating CHD, and (2) whether some of the therapy’s possible effect may be due to high doses of vitamin and mineral supplements, which are often given with EDTA chelation therapy when practiced in the community.

What was the purpose of the study?

The purpose of the study was to determine the safety and efficacy of EDTA chelation therapy for treating CHD. TACT was designed to see whether EDTA chelation therapy and/or high-dose vitamin/mineral supplements are safe and effective in treating individuals with prior heart attacks. Specifically, the researchers sought to determine if EDTA chelation and/or high-dose vitamin supplements improved event-free survival (length of time without a cardiovascular event, such as a heart attack) in participants who were also treated with the gold standard approach for their cardiovascular disease.

The investigators looked at several markers of improvement, or endpoints, to make these determinations. The primary endpoint in the trial was a composite of:

• All causes of death
• Heart attack
• Stroke
• Hospitalization for angina
• Coronary revascularization

Secondary endpoints included:

• Cardiac death, or nonfatal heart attack, or nonfatal stroke
• The individual components of the primary endpoint
• The safety of the therapy
• Health-related quality of life
• Cost effectiveness

What was the basic design of the study?

The study had a placebo-controlled, double-blind design that included 1,708 participants aged 50 years and older with a prior heart attack. Its purpose was to test whether EDTA chelation therapy and/or high-dose vitamin therapy is effective for the treatment of CHD.

EDTA chelation therapy, as practiced in the community, often includes administration of high doses of antioxidant vitamin and mineral supplements. In order to test whether some of the therapy’s effect may be attributable to vitamin/mineral supplements or to the EDTA solution itself, the investigators randomly assigned participants to receive either EDTA chelation solution or placebo. Then, the patients in these two groups were again randomly selected to receive either low-dose or high-dose vitamin/mineral supplements.

The EDTA chelation therapy or placebo solution was delivered through 40 intravenous (into the veins) infusions. The first 30 infusions were delivered on a weekly basis and the last 10 were delivered every 2 to 8 weeks. Following the infusion phase, participants had contact with study staff at 3-month intervals until the study was complete.

What were the key results of the study?

The researchers concluded that:

• TACT provides evidence that a regimen of 40 infusions of disodium EDTA modestly reduced the risk of some cardiac events in adults who had previously had a heart attack. This treatment effect lasted over the 5-year follow-up period.
• Overall, those receiving chelation had an 18 percent reduced risk of subsequent cardiac events such as heart attack, stroke, hospitalization for angina, or coronary revascularization. A cardiac event occurred in 222 (26 percent) of the chelation group and 261 (30 percent) of the placebo group.
• These results are not, by themselves, sufficient to support the routine use of chelation as post-heart attack therapy.

The researchers compared the results for people who did or did not have diabetes. People with diabetes made up 37 percent of the total group. The researchers found that:

• Among patients with diabetes, those receiving chelation had a lower risk of cardiovascular events such as heart attack, stroke, hospitalization for angina, or coronary revascularization. Events occurred in 25 percent of the patients with diabetes who received EDTA chelation and in 38 percent of those who received placebo. Death from any cause was 43 percent lower in those patients with diabetes who received chelation.
• Among patients who did not have diabetes, chelation therapy was not associated with a reduction in cardiovascular events.
• These results are not, by themselves, sufficient to support the routine use of chelation as post-heart attack therapy in people with diabetes.

What did TACT cost?

TACT cost approximately $32 million over the course of the 10 years it took to conduct and complete it.

What did the chelation infusions contain?

For TACT, the active, 10-component chelation solution was selected to closely match the standard regimen used by chelation practitioners. The solution contained up to 3 g disodium EDTA, 7 g ascorbate, 2 g magnesium chloride, 100 mg procaine hydrochloride, 2,500 U 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. The placebo solution consisted of 500 mL of normal saline and 1.2 percent dextrose.

The infusions were prepared at a central pharmacy for the study and then shipped to the study sites in refrigerated containers.

How was patient safety monitored?

A number of safety mechanisms were in place, including a protocol with standard doses of disodium EDTA based on kidney function. Oversight by a Clinical Coordinating Center ensured that the sites did not give infusions to patients for whom they might pose a risk because of their medical conditions and did not give infusions too rapidly. An NIH-appointed Data and Safety Monitoring Board monitored patient safety, treatment effects, and the conduct of the trial. In addition, NIH, the U.S. Food and Drug Administration (FDA), and local or central institutional review boards provided oversight.

Were any adverse events reported?

Overall, 38 people (16 percent) receiving chelation and 41 people (15 percent) receiving placebo cited an adverse event as the cause of discontinuing study infusions. There were 4 unexpected severe adverse events that were possibly or definitely attributed to study therapy—2 in the chelation group (1 death), and 2 in the placebo group (1 death). Heart failure was reported in 57 (7 percent) chelation patients, and 71 (8 percent) placebo patients. A total of 55,222 infusions were given throughout the course of the study. Of those infusions, 330 (0.6 percent) were administered at least 30 minutes too rapidly. Hypocalcemia, prior to an infusion, was reported in 52 (6.2 percent) chelation patients and 30 (3.5 percent) placebo patients. One patient had hypocalcemia associated with muscle cramping that led to an emergency department visit. 

Where did the study take place?

The study was conducted at 134 research sites located across the United States and Canada. Per standard clinical trial procedure, the sites were selected based on a thorough review of qualifications by the study team and required approval of the study by their local or central institutional (ethical) review boards.

Who participated in TACT?

Over the course of the study, 1,708 patients were randomized after signing informed consent—839 patients to chelation and 869 patients to placebo. The study recruited participants who were 50 years of age or older, had had a heart attack at least 6 weeks prior to evaluation, and had not had chelation therapy within the past 5 years. The participants also could not have:

• History of allergic reactions to EDTA or any of the therapy’s components
• Coronary or carotid revascularization procedures within the past 6 months or a scheduled revascularization
• History of cigarette smoking within the last 3 months
• Childbearing potential
• History of liver disease
• Diagnoses of additional medical conditions that could limit patient survival, such as cancer

On average, TACT participants were 65 years old. A total of 18 percent of participants were women and 9 percent were minorities. Participants’ heart attacks had, on average, occurred 4.6 years before enrollment. The study population had a high rate of diabetes (31 percent), prior coronary revascularizations (83 percent), and use of evidence-based medications, such as aspirin (84 percent), beta-blockers (72 percent), and statins (73 percent).

About the Second Study

What were the aims of the second Trial to Assess Chelation Therapy (TACT2)?

TACT2 repeated the first TACT study, but only in patients with diabetes and a prior heart attack, to see if the apparent benefit of EDTA chelation therapy in this group of patients could be confirmed.

Because it had been proposed that the benefits of chelation therapy, if confirmed, might be due to removal of lead and cadmium, TACT2 included measurements of participants’ blood lead and urine cadmium levels.

The three specific aims of the study were to:

• Determine whether the chelation-based treatment improves cardiovascular event-free survival in this group of patients
• Determine whether the treatment reduces mortality in this group of patients
• Perform a cost-effectiveness analysis of the TACT2 chelation strategy

Why was a second trial needed?

The second trial was needed to see whether the unexpected apparent benefit of chelation therapy in patients with heart disease and diabetes in the first TACT study could be confirmed.

Who sponsored TACT2?

The National Institutes of Health (NIH) sponsored TACT2. The study was co-funded by four NIH agencies: NCCIH, NHLBI, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute of Environmental Health Sciences (NIEHS).

Where did the trial take place?

The trial took place at 88 sites in the United States and Canada. Most of the sites were “conventional medicine” sites with research experience rather than sites that administer chelation therapy as a complementary health approach.

How many people participated, and who was eligible?

TACT2 included 1,000 people, 959 of whom actually received EDTA or placebo infusions. To be eligible for the study, people had to be 50 or older, have diabetes, have survived a heart attack, and meet other eligibility criteria, similar to those for TACT participants. People who had participated in TACT were not eligible to participate in TACT2.

What was the basic design of the study?

The basic design was the same in most respects as that of TACT, except that all participants had diabetes as well as meeting the other eligibility criteria. Just as in TACT, the investigators randomly assigned participants to receive either EDTA chelation solution or placebo and either high-dose or low-dose vitamin supplements. The outcomes assessed in TACT2 were similar to those in TACT, except for the addition of outcomes related to lead and cadmium. Participants were followed for a median of 48 months.

What did TACT2 cost?

The TACT2 study cost approximately $46 million.

What were the key results of the study?

EDTA chelation did not reduce cardiovascular events in TACT2. Cardiovascular events occurred in 172 (35.6 percent) of participants who received EDTA chelation solution and 170 (35.7 percent) of those who received placebo. Cardiovascular death, myocardial infarction, or stroke events occurred in 89 participants (18.4 percent) in the chelation group and 94 (19.7 percent) in the placebo group. Death from any cause occurred in 84 participants (17.4 percent) in the chelation group and 84 participants (17.6 percent) in the placebo group. There were no significant differences between the chelation and placebo groups in any of these outcomes.

TACT2 did not reproduce the results of TACT in patients with diabetes who have had a heart attack, and the TACT2 results do not support using EDTA chelation to reduce the risk of cardiovascular events in this group of people.

EDTA chelation reduced blood lead levels in TACT2 from a median of 9.03 μg/L at baseline to 2.46 μg/L at the time of the last infusion, a statistically significant 61 percent reduction. Blood lead levels did not change significantly in the placebo group. Urine cadmium levels increased substantially right after each chelation treatment. Thus, EDTA therapy was effective in chelating both lead and cadmium and promoting their excretion.

The results for the high-dose vitamin/mineral component of TACT2 have not yet been reported.

Why did the results of TACT2 differ from the results for people with diabetes in TACT?

The reason for the difference is not yet understood. Further analyses of the data may provide an explanation.

The researchers who conducted TACT2 suggested that differences between the TACT and TACT2 study participants might have contributed to the difference in the results between the two studies. The TACT2 participants had more advanced heart disease and higher cardiovascular event rates than those in TACT and may have been exposed to lower levels of lead.

Background

What is coronary heart disease (CHD)?

CHD (also called coronary artery disease or ischemic heart disease) is a type of heart disease where the arteries of the heart cannot deliver enough oxygen-rich blood to the heart. It is the most common type of heart disease in the United States, affecting about 20.5 million U.S. adults.

CHD is often caused by a buildup of cholesterol inside the lining of the coronary arteries, forming plaque, which can partially or totally block blood flow. Symptoms may differ from person to person, and many people do not have symptoms until they develop chest pain or have a heart attack.

Factors that can increase the risk of developing CHD include older age, certain aspects of environment and occupation (such as exposure to toxins, long periods of sitting, or stress), family history and genetics, lifestyle habits (such as physical inactivity, not getting enough good-quality sleep, smoking or long-term exposure to secondhand smoke, stress, and unhealthy eating patterns), and other medical conditions that affect the heart and blood vessels.

Visit the NHLBI website to learn more about coronary heart disease (CHD).

How is CHD diagnosed and treated?

Diagnosis of CHD is based on symptoms, the patient’s medical and family history, risk factors, and the results from tests and procedures. Screening tests and risk assessments for CHD should begin at around age 20 even for people who do not have risk factors; they may begin at a younger age for those who do have risk factors. Screening may include assessment of risk factors, determining whether the person has overweight or obesity, checking blood pressure, and performing blood tests for high blood cholesterol, high blood triglycerides, and diabetes. 

Treatment for CHD may include heart-healthy lifestyle changes (such as choosing heart-healthy foods, being physically active, not smoking, getting enough good-quality sleep, aiming for a healthy weight, getting blood pressure and cholesterol into a healthy range, controlling blood sugar, and managing stress). Medicines may be prescribed to widen blood vessels and help the heart beat with less force or to control risk factors such as high cholesterol. Some people with serious CHD may need medical procedures or heart surgery.

What is EDTA chelation therapy?

Chelation therapy is a process in which a substance is delivered intravenously (through the veins) to bind metals or minerals so they can be removed from the body via urination.

In the case of EDTA chelation therapy, the substance that binds and removes metals and minerals is the salts of EDTA (also called ethylene diamine tetraacetic acid or edetate), a synthetic amino acid. TACT and TACT2 used the salt disodium EDTA under an FDA license as an Investigational New Drug (IND). Although disodium EDTA is not approved by the FDA to treat CHD, some physicians and alternative medicine practitioners have recommended its use in chelation as a way to treat CHD.

What are the possible side effects of EDTA chelation therapy?

A common side effect is a burning sensation at the site where EDTA is delivered into a vein. Side effects may also include fever, headache, nausea, and vomiting. Serious potential side effects include hypocalcemia (low blood calcium levels) and toxicity to the kidneys. Other possible side effects include hypotension (abnormally low blood pressure), mineral and vitamin deficiencies, and heart failure due to fluid overload.

How commonly is chelation therapy used?

The 2007 National Health Interview Survey, conducted by the Centers for Disease Control and Prevention, found that 111,000 adults 18 years of age and older used chelation therapy as a form of complementary medicine in the previous 12 months.

Publications From the TACT Studies

For More Information

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Last Updated: August 2024