Research evidence and proof of effectiveness of IV chelation in patient’s with diabetes and heart disease

ARTICLES AND PAPERS ON CHELATION TACT Trial Update 2013 Read about the findings from the NIH sponsored Trial to Asess Chelation Therapy.

ABOUT EDTA CHELATION

Trends Cardiovasc Med. 2014 Aug;24(6):232-40. doi: 10.1016/j.tcm.2014.06.002. Epub 2014 Jun 12. Chelation therapy and cardiovascular disease: connecting scientific silos to benefit cardiac patients.
Peguero JG1, Arenas I1, Lamas GA2.
Author information
Abstract
Medical practitioners have treated atherosclerotic disease with chelation therapy for over 50 years. Lack of strong of evidence led conventional practitioners to abandon its use in the 1960s and 1970s. This relegated chelation therapy to complementary and alternative medicine practitioners, who reported good anecdotal results. Concurrently, the epidemiologic evidence linking xenobiotic metals with cardiovascular disease and mortality gradually accumulated, suggesting a plausible role for chelation therapy. On the basis of the continued use of chelation therapy without an evidence base, the National Institutes of Health released a Request for Applications for a definitive trial of chelation therapy. The Trial to Assess Chelation Therapy (TACT) was formulated as a 2 × 2 factorial randomized controlled trial of intravenous EDTA-based chelation vs. placebo and high-dose oral multivitamins and multiminerals vs. oral placebo. The composite primary endpoint was death, reinfarction, stroke, coronary revascularization, or hospitalization for angina. A total of 1708 post-MI patients who were 50 years or older with a creatinine of 2.0 or less were enrolled and received 55,222 infusions of disodium EDTA or placebo with a median follow-up of 55 months. Patients were on evidence-based post-MI medications including statins. EDTA proved to be safe. EDTA chelation therapy reduced cardiovascular events by 18%, with a 5-year number needed to treat (NNT) of 18. Prespecified subgroup analysis revealed a robust benefit in patients with diabetes mellitus with a 41% reduction in the primary endpoint (5-year NNT = 6.5), and a 43% 5-year relative risk reduction in all-cause mortality (5-year NNT = 12). The magnitude of benefit is such that it suggests urgency in replication and implementation, which could, due to the excellent safety record, occur simultaneously. Copyright © 2014 Elsevier Inc. All rights reserved.

Complementary and alternative medications are widely used, including therapies aimed at cardiovascular disease.1 These treatments are not generally accepted by the mainstream medical community, although they may be based on folk remedies. However, because many widely accepted medical therapies have been discovered from plants and other natural products, it would be foolish to dismiss the possibility that alternative treatments are actually effective. Most of these therapies are “unproven,” but that does not mean that they are ineffective, just that they have not been tested rigorously for efficacy in a proper scientific study. The National Center for Complementary and Alternative Medicine was designed to assess generally used yet unorthodox treatments. The concern about this center's mission is that true believers in alternative therapy might not accept a result from a clinical trial that they do not like—many of them are suspicious of science, after all. The expectation was that results from a properly designed scientific study would be accepted by the mainstream medical community, who are swayed by evidence rather than belief. Ironically, the results of the Trial to Assess Chelation Therapy (TACT) have been greeted with widespread skepticism, even disdain, from the larger scientific community.

Chelation therapy for cardiovascular disease has been controversial for years,1 and there have long been calls for a randomized trial of chelation to settle whether it is effective. TACT was designed to test rigorously if chelation therapy improved outcomes in patients with coronary disease. TACT was a double-blind, 2 × 2 factorial randomized controlled trial funded by the National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine. A total of 1,708 stable patients 50 years or older with a prior myocardial infarction (MI) were randomized to receive (a) either 40 infusions of disodium ethylenediaminetetraacetic acid chelation or infusions of placebo and (b) either oral high-dose vitamin and mineral therapy or oral placebo. The overall results showed a significant reduction in the primary end point (death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) in the chelation group (26%) compared with the placebo group (30%).2 Patients with diabetes had a greater reduction in the primary end point than did patients without diabetes and were later shown to have consistent reductions in the individual components of the primary end point.3

The article by Lamas et al (2014) in this month's issue of the American Heart Journal extends those results by reporting on outcomes in the 4 randomized factorial groups for all 1,708 randomized patients and the 633 with diabetes. They find a graded response in the primary end point across the 4 groups: 32% in the chelation + high-dose vitamin (double active) group, 34% in the chelation + placebo vitamin group, 37% in the placebo infusion + active vitamin group, and 40% in the placebo infusions + placebo vitamin (double placebo) group. The reduction in primary end point by double active treatment compared with double placebo was significant (hazard ratio, 0.74; 95% CI, 0.57-0.95; P = .016). In patients with diabetes, the primary end point reduction from double active therapy compared with double placebo was more pronounced (hazard ratio, 0.49; 95% CI, 0.33-0.75; P < .001). In both the total study population and the patients with diabetes, the groups with one active therapy had an intermediate number of events and were not statistically significantly different from the double placebo group.

This additional analysis from TACT strengthens the credibility of the overall results and suggests that chelation therapy might be particularly beneficial in post-MI patients with diabetes. Because the benefit was seen in diabetic patients mostly being treated at baseline with evidence-based medical therapy, these results suggest that mechanisms may be operating that complement established secondary prevention therapies, although the trial was not designed to elucidate potential mechanisms.

Implications These findings from TACT were surprising, unexplained, and, to some, frankly unwelcome. Clinical trial pundits not associated with TACT issued sharp attacks on its design and conduct.4, 5 The criticisms include having unskilled (or worse) investigators at complementary and alternative medicine sites (nearly 2 dozen of trial coinvestigators have been disciplined by state medical boards for infractions ranging from insurance fraud to providing ineffective treatments); a high rate of withdrawal of consent with differential dropout (overall 17%, more from the placebo than the chelation group); lack of equipoise by investigators who advocate chelation and unblinded treatment assignments, including “soft end points” in the primary composite end point (coronary revascularization and hospitalization for angina); and misrepresenting the chelation agent on the informed consent form. The TACT investigators have also been defended,6 and the editors of the Journal of American Medical Association (JAMA) wrote a special article justifying their decision to publish the main results.7 The TACT investigators themselves interpreted the trial results cautiously, stating that their results are of potential clinical relevance but do not constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI patients with diabetes.3 They appropriately support efforts to replicate the findings and define the mechanisms of benefit.

When evidence conflicts with expectations, the findings are typically discounted. This response is rational from a Bayesian perspective—if the pretest probability (read “pretrial beliefs”) is low, a positive test (trial) should revise the posttest probability upward, but the result is not conclusive. Scientific paradigms shift only after the weight of evidence builds up sufficiently to move from hypothesis to proven fact. There are some classic examples of clinical trials that overturned conventional wisdom. Postmenopausal estrogen therapy was believed to prevent coronary disease events based on observational studies, but randomized clinical trials showed harm rather than benefit.8, 9 Antiarrhythmic drug therapy suppresses ventricular ectopy after MI and was therefore widely believed to reduce the risk of sudden cardiac death, but a randomized controlled trial showed that it did not.10 β-Blockers were contraindicated in heart failure until randomized controlled trials proved they were indicated.11, 12, 13 There are many examples of interventions commonly used—or not used—in practice that failed to show the expected result when tested in carefully conducted randomized controlled trials. In the case of TACT, the intervention (chelation therapy) is not commonly used in practice and most physicians expected the trial to show no benefit, yet a benefit was seen. Either way, we should not let our biases blind us to the possibility that unexpected results might provide an important clue for a new approach.

It is critical to use the scientific method to test our beliefs against the evidence. Simply dismissing results that we did not expect would ignore opportunities to expand knowledge and the armamentarium of effective therapies. This latest report is a useful extension of the previously published work from TACT and should prompt new research to replicate the initial provocative findings and base decisions about chelation on strong scientific evidence, not on beliefs, either pro or con.

Chelation Therapy

Gervasio A. Lamas, MD
From Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, FL.
Correspondence to Gervasio A. Lamas, MD, FAHA, Columbia University Division of Cardiology, Mount Sinai Medical Center

Introduction Don’t cringe when you hear the term chelation (key-LAY-shun) therapy. If you have heard about it at all, you may have heard that it is alternative medicine, quackery, expensive, and even dangerous. New research funded by the National Institutes of Health is suggesting that this old treatment has some real life in it and that it may particularly benefit patients with diabetes mellitus and prior heart attacks.

What Is Chelation Therapy? Chelation therapy was first used in the early 20th century to treat metal poisoning. The treatment involves administering a drug called a chelator, which has a magnetically charged pocket that can “grab” a metal and hang onto it, kind of like a baseball mitt with a magnet in its pocket, allowing the metal to be excreted in the urine. One chelator, calcium ethylenediaminetetraacetic acid (EDTA), is approved by the US Food and Drug Administration to treat lead poisoning. Alternative medicine practitioners have been using a similar chelator, disodium EDTA, to treat heart disease, claiming to see benefits, since the 1950s.

Disodium EDTA chelation therapy is usually administered intravenously each week for 20 to 40 sessions. Each intravenous infusion may last hours. In spite of the expense and tedium, the 2008 National Health Statistics Report stated that 111 000 people used chelation in 2007.

What Does My Doctor Think About Chelation? Major cardiology organizations have published statements discouraging the use of chelation. These opinions were formed in the 1960s and 1970s, when the doses and rates of administration of EDTA chelation had not been standardized, and there were safety problems, including kidney problems and even deaths. These opinions were so strong that until 2002 no large-scale, clinical trial had been funded that could determine whether EDTA chelation harmed or benefitted cardiac patients.

So What Is New About Chelation in 2015? There are reasons to think that chelation to remove metals might treat or prevent heart disease.1 Some complications of diabetes mellitus may be caused by chemical reactions that happen to the excess sugar in the blood. These reactions are catalyzed, or facilitated, by metals. The environment is polluted with metals that are toxic to our systems. Lead (gasoline, plumbing), arsenic (well water, rice, apple juice), mercury (many fish), and cadmium (from rechargeable batteries) are among the top 10 most toxic substances listed by the US government. EDTA chelates lead and cadmium.

Concurrent with these conceptual developments and because of the large number of Americans receiving chelation therapy, in 2002, the National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute funded a $30 million clinical trial of chelation therapy in patients 50 years of age or older with a prior heart attack and good kidney function to finally understand whether EDTA chelation for coronary disease was safe and effective. So, the Trial to Assess Chelation Therapy (TACT) was born.

TACT enrolled 1708 patients who were at least 50 years old and had had a prior heart attack. The proposed treatment was intensive: 40 intravenous infusions, 3 hours each, all given over a little more than a year. Half of the patients received EDTA chelation; the other half received a saltwater placebo. Overall, patients received 55 222 intravenous infusions in 134 offices and hospitals across the United States and Canada. Nearly a decade later, on August 15, 2012, we learned the results of our work. Did chelation work to reduce heart events in a vulnerable population with a prior heart attack? It turns out that it did. And it was safe.

Results of TACT Overall, there was an 18% reduction in heart events (death, another heart attack, stroke, stenting or bypass, and hospitalization for heart pains) by EDTA infusions above and beyond that provided by our effective treatments, including statins and aspirin.2 When the group who took the EDTA infusions plus oral vitamins was analyzed, the reduction was 26% compared with placebo.3 The effect was even more striking in patients with diabetes mellitus, in whom there was a 41% reduction in clinical events (Figure), including a 43% reduction in deaths over 5 years.4 There is nothing comparable in diabetes therapies.

I Had a Heart Attack and I Have Diabetes Mellitus; Should I Receive Chelation? The landscape for chelation therapy has changed, and environmental toxins may emerge as a modifiable risk factor for heart disease. The US Food and Drug Administration reviewed the TACT in a positive light but encouraged us to carry out another study to confirm these results (TACT2 is being planned). The American Heart Association, in its latest guidelines, has upgraded chelation from Class III (never ever do) to Class IIb (probably not effective). So, the “official” answer is no.

However, this is an emerging technology, and I believe our data. Clinicians sometimes race ahead of official guidelines. When asked, I recommend that patients seek their doctor’s advice after their doctor has read the TACT articles referenced here. If patients with diabetes mellitus and a prior heart attack want chelation, I do not discourage them like I used to. And for high-risk patients in hospitals that offer chelation as a therapeutic choice like mine, I recommend it. Finally, if your hospital is participating in the upcoming TACT2, currently in the very early planning phase, please get involved in the research. We still have a lot to learn.

Sources of Funding The National Heart, Lung, and Blood Institute and the National Center for Complementary and Integrative Health provided funding and oversight (grants U01AT001156 and U01HL092607).

Footnotes The information contained in this Circulation Cardiology Patient Page is not a substitute for medical advice, and the American Heart Association recommends consultation with your doctor or healthcare professional. © 2015 American Heart Association, Inc.

Efficacy of DMSA Therapy in a Sample of Arab Children with Autistic Spectrum Disorder.

Blaucok-Busch E1, Amin OR, Dessoki HH, Rabah T.

Abstract

OBJECTIVE: the aim of this study was to provide evidence that DMSA detoxification treatments cause a reduction of the heavy metal burden in the autistic, and that this reduction lessens neurological symptoms associated with ASD (Autistic Spectrum Disorder).

METHOD: The participants were 44 children, age 3 to 9 years of age, with Autistic Spectrum Disorder (ASD) according to Diagnostic and Statistical Manual of Mental Disorders 4t Edition, (DMS-IV). The severity of the autistics symptomatologiy had been measured by the Childhood Autism Rating Scale (SCARS). We collected urine samples before and after the DMSA challenge test, comparing urine metal output. We also compared the results of the DMSA detoxification(=the urine challenge test) with behavioral effects, typical for ASD.

RESULTS: The DMSA challenge test increased the urine metal output for a number of potentially toxic metals. Statistically significant difference were noted between the baseline urine and DMSA challenge test regarding the level of cadmium, mercury, and lead (P=0.006, P=0.049, and P=0.008 respectively). We also noted that behavioral effects, typical for ASD (autism spectrum disorders) were reduced with this method of detoxification. A comparison between CARS Subscales and Total Score before and after a 6-month chelation program showed greatest improvements for Verbal and nonverbal communication (P <0.001), Taste, Smell and Touch (P 0.001) and Relating to People (P 0.005). Other improvements were noted for Adaptation to Change and Improvement.

CONCLUSION: DMSA chelation increased the urinary output of toxic and neurotoxic metals. Our data supports evidence that detoxification treatment with oral DMSA has beneficial effect on ASD patients.