About the First Study

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

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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. The National Institutes of Health’s (NIH) 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 study of chelation therapy. It was designed to be large enough to detect if there are any moderate benefits or risks associated with the therapy.

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Why did NCCIH and NHLBI decide to study this therapy?

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In addition to effective standard therapies, such as lifestyle modifications, medications, and surgical procedures, some patients with coronary heart disease (CHD) seek out EDTA chelation therapy as a treatment option based on anecdotal reports of improved symptoms in patients with heart disease. Prior to TACT, the evidence cited in support of using EDTA chelation therapy was in the form of case reports and case series.

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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 regimen when practiced in the community.

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What was the purpose of the study?

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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, they 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.

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

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• All causes of death

• Heart attack

• Stroke

• Hospitalization for angina

• Coronary revascularization.

 

Secondary endpoints included:

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• 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?

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The study was 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.

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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.

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The EDTA chelation therapy or placebo solution was delivered through 40 intravenous (into the veins) infusions that were administered over a 28-month course of treatment. The first 30 infusions were delivered on a weekly basis and the last 10 were delivered during a maintenance phase every two to eight weeks. Following the infusion phase, participants had contact with study staff at 3-month intervals until the study was complete.

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What were the key results of the study?

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The researchers concluded that:

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• 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 followup period.

• Overall, those receiving chelation had an 18% reduced risk of subsequent cardiac events such as heart attack, stroke, hospitalization for angina, or coronary revascularization. A cardiac event occurred in 222 (26%) of the chelation group and 261 (30%) 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% of the total group. The researchers found that:

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• 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% of the patients with diabetes who received EDTA chelation and in 38% of those who received placebo. Death from any cause was 43% 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?

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TACT cost approximately $31.6 million over the course of the 10 years it took to conduct and complete it.

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What did the chelation infusions contain?

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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% dextrose.

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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?

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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 or were infused 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.

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Were any adverse events reported?

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Overall, 38 people (16%) receiving chelation and 41 people (15%) 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%) chelation patients, and 71 (8%) placebo patients. A total of 55,222 infusions were given throughout the course of the study. Of those infusions, 330 (0.6%) were administered at least 30 minutes too rapidly. Hypocalcemia, prior to an infusion, was reported in 52 (6.2%) chelation patients and 30 (3.5%) placebo patients. One patient had hypocalcemia associated with muscle cramping that led to an emergency department visit.

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Where did the study take place?

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The study was conducted at 134 research sites located across the United States and Canada. The research sites represented a mix of clinical settings—university or teaching hospitals, clinical practices or cardiology research centers, and chelation practices. 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.

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Who participated in TACT?

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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 at least 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:

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• 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 otherwise limit patient survival, such as cancer.

 

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

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About the Second Study

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

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TACT2 will repeat 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 can be confirmed.

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The three specific aims of the study are to:

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• 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 is a second trial needed?

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

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The results will help the Food and Drug Administration (FDA) determine whether disodium EDTA chelation therapy should be approved to reduce the risk of further cardiovascular events in patients who have both coronary artery disease and diabetes and cardiovascular and diabetes guideline committees will add this to a list of known effective therapies for treatment of cardiovascular disease in patients with diabetes.

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Who is sponsoring TACT2?

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The National Institutes of Health (NIH) is sponsoring TACT2. It is being co-funded by four NIH agencies: National Center for Complementary and Integrative Health (NCCIH), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Institute of Environmental Health Sciences (NIEHS).

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Where will the trial take place?

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The trial will take place at more than 100 sites in the United States and Canada. You can see a map showing the locations of the study sites on the TACT2 Web site.

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How many people will participate, and who is eligible?

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TACT2 will include 1,200 people. To be eligible for the study, people must be 50 or older, have diabetes, have survived a heart attack, and meet other eligibility criteria.

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Where can patients enroll in the study?

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Contact the study team through their Web site, www.tact2.org. More information is also available on clinicaltrials.gov.

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Background

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What is coronary heart disease?

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Coronary heart disease (CHD) is the most common form of heart disease, which is the leading cause of death among American men and women. Each year nearly 380,000 Americans die from CHD. In CHD the coronary arteries, the vessels that provide oxygen-rich blood to the tissues of the heart, become blocked by deposits of a waxy substance called plaque. As plaque builds, the arteries become narrower and less oxygen and nutrients are transported to the heart. CHD can lead to serious problems, such as angina (pain caused by not enough oxygen-carrying blood reaching the heart) and heart attack. A heart attack occurs if the flow of oxygen-rich blood to a section of heart muscle is cut off. If blood flow is not restored quickly, the affected section of heart muscle begins to die. Without quick treatment, a heart attack can lead to serious health problems or death.

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Factors that can increase the risk of developing CHD include:

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• High blood pressure

• High blood cholesterol levels

• Smoking

• Overweight or obesity

• Physical inactivity

• Diabetes

• Insulin resistance

• Metabolic syndrome

• Unhealthy diet

• Family history of CHD

• Older age.

 

Symptoms of CHD can include chest pain, shortness of breath, lightheadedness, cold sweats, or nausea, but not everyone with CHD has symptoms.

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How is CHD diagnosed and treated?

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Diagnosis of CHD is based on personal medical and family histories, risk factors for CHD, a physical exam, and the results from tests and procedures. Doctors who suspect CHD may recommend one or more tests, such as those that check levels of fats, cholesterol, and sugar; electrocardiograms (EKG) to check the heart’s electrical activity; “stress” tests to record the heartbeat during exercise; nuclear scanning to check for damaged areas of the heart; and angiography to see if there are blockages or narrowings in the blood vessels that feed the heart. Treatment of CHD includes lifestyle changes—stopping smoking for patients who smoke, following a heart-healthy diet, and engaging in a prescribed exercise program. Medications may also be prescribed, such as aspirin to prevent heart attacks, medications that decrease the workload on the heart, or medicines that reduce blood cholesterol levels or blood pressure. If these efforts are not effective, a patient may need to have the narrowed or blocked arteries re-opened through a procedure called percutaneous coronary intervention (PCI) or bypassed through surgery. PCI involves threading a thin tube into an artery and expanding a balloon-like apparatus as a way to increase the size of the artery so more blood can flow. Bypass surgery is used to treat severe blockages by using veins or arteries from other areas of the body to divert blood flow around the blocked coronary arteries.

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To learn more about CHD and its diagnosis and treatment visit: www.nhlbi.nih.gov/health/health-topics/topics/cad/.

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What is EDTA chelation therapy?

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Chelation is a chemical process in which a substance is used to bind molecules, such as metals or minerals, and hold them tightly so that they can be removed from a system, such as the body. In medicine, chelation has been scientifically proven to rid the body of excess or toxic metals. For example, a person who has lead poisoning may be given chelation therapy in order to bind and remove lead from the body before it can cause damage.

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In the case of EDTA chelation therapy, the substance that binds and removes metals and minerals is the salts of EDTA (ethylene diamine tetra-acetic acid), a synthetic, or man-made, amino acid that is delivered intravenously. EDTA was first used in the 1950s for the treatment of heavy metal poisoning. Calcium disodium EDTA chelation removes heavy metals and minerals from the blood, such as lead, iron, copper, and calcium, and is approved by the FDA for use in treating lead poisoning and toxicity from other heavy metals. Rather than testing calcium disodium EDTA, TACT used another salt, disodium EDTA, under an FDA license as an Investigational New Drug (IND). Although disodium EDTA it 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.

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What are the possible side effects of EDTA chelation therapy?

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The most common side effect is a burning sensation at the site where EDTA is delivered into a vein. Rare side effects can include fever, headache, nausea, and vomiting. Even more rare are serious and potentially fatal side effects that can include heart failure, a sudden drop in blood pressure, abnormally low calcium levels in the blood (hypocalcemia), permanent kidney damage, and bone marrow depression (meaning that blood cell counts fall). Hypocalcemia and death may occur, particularly if disodium EDTA is infused too rapidly. Reversible injury to the kidneys, although infrequent, has been reported with EDTA chelation therapy. Other serious side effects can occur if EDTA is not administered by a trained health professional.

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How commonly is EDTA chelation therapy used?

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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.

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Publications From the TACT Studies

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• Escolar E, Lamas GA, Mark DB, 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: Cardiovascular Quality and Outcomes. 2014;7(1):15–24.

• Lamas GA, Boineau R, Goertz C, et al. EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: the factorial group results of the Trial to Assess Chelation Therapy. American Heart Journal. 2014;168(1):37–44.e5.

• Lamas GA, Boineau R, Goertz C, et al. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Annals of Internal Medicine. 2013;159(12):797–805.

• Lamas GA, Goertz C, Boineau R, et al. Design of the trial to assess chelation therapy (TACT). American Heart Journal. 2012;163(1):7–12.

• Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309(12):1241–1250.

 

 

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