Brief History and Overview
Chelation is the administration of chelating agents to remove heavy metals from the body. Chelation treatment was first reported to have clinical benefits in patients with symptomatic coronary artery disease (CAD) through a serendipitous set of observations starting in 1956. Subsequent clinical investigations of chelation, however, were mixed and serious research in this area stopped in the early 1960s.
Alternative medicine practitioners continued to use chelation for prevention of complications of atherosclerosis based on their anecdotal experiences. Because of the lack of proof of benefit and the implausibility of the proposed mechanism of benefit (removal of calcium from complex atherosclerotic plaques), most major mainstream medical organizations during the 1980s to 1990s made policy statements against chelation.
The first Trial to Assess Chelation Therapy (TACT1) was developed in response to a Request for Applications from the National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart Lung and Blood Institute (NHLBI). At the time, members of the U.S. Congress expressed concern that chelation use was widespread but there were no reliable data on either safety or efficacy. Our research team, led by Drs. Gervasio Lamas, Kerry Lee, and Daniel Mark, was awarded the TACT1 grant in 2002.
TACT1 was completed in 2012 (enrolling 1708 patients) and showed that a combination of up to 40 infusions with intravenous (IV) disodium EDTA plus oral multivitamins and multiminerals (OMVM) compared with intravenous and oral placebo led to a significant reduction in the time to first recurrent cardiovascular event in patients with prior myocardial infarction, age 50 or older, already treated with standard evidence-based medical therapies.
In the subgroup with diabetes (633 patients), the results were dramatic: the chelation-based strategy reduced cardiac events by 51% and reduced total mortality by 43%.
In response to the data from TACT1, the American College of Cardiology/American Heart Association granted chelation a 2b indication for treatment of chronic ischemic heart disease.
As a result of the TACT1 findings, and because of the public health impacts of cardiovascular disease and of diabetes, we were encouraged by the National Institutes of Health (NIH) and the FDA to confirm the results of TACT1. After key discussions with the NIH, FDA, and leaders in the field of cardiology, we elected to perform TACT2 in patients with diabetes, representing the patients in TACT1 with the greatest benefit. This refinement will reduce the size, duration, and cost of the clinical trial relative to TACT1.
In TACT1, a factorial design examined the two major components of the chelation strategy in common use by alternative medicine practitioners, EDTA chelation and oral multivitamins and multiminerals (OMVM). Because our analyses found those two therapies provided additive benefits, both the NIH and FDA supported the decision to test the strongest strategy in TACT2, chelation plus OMVM, to promote the most efficient trial possible.
TACT2 will enroll 1200 patients with diabetes who are 50 years of age or older, have had a heart attack (prior myocardial infarction [MI]), and have good kidney function (serum creatinine 2.0 mg/dL or less). Patients will be randomly allocated to receive either chelation plus OMVM, or placebo (inactive substance). All patients will be followed for ~ 5 years.
The specific aims of TACT2 are:
- To determine if the chelation-based strategy in patients with diabetes and prior MI improves event-free survival;
- To determine if the chelation-based strategy in patients with diabetes and prior MI reduces mortality;
- To perform an economic analysis of the TACT2 chelation strategy.
Who is leading TACT2?
Dr. Lamas is the Chairman of Medicine at Mount Sinai Medical Center and Chief of the Columbia University Division of Cardiology at Mount Sinai Medical Center. His interests include the treatment and prevention of cardiovascular disease. During the last decade, he has enrolled thousands of patients in more than a dozen U.S. and international trials in order to improve cardiac care and prevent death and disability from heart disease. He served as Chairman of the Mode Selection Trial in Sinus Node Dysfunction (MOST), a trial that revolutionized cardiac pacemakers. He has served as Co-Chairman for the Occluded Artery Trial (OAT), and Study Chair for the Trial to Assess Chelation Therapy (TACT), a $30 million trial sponsored by the National Institutes of Health. He has authored over 300 scientific publications, and maintains an active clinical practice in Miami Beach and Key Biscayne.
Dr. Anstrom is an Associate Professor in the Department of Biostatistics and Bioinformatics at Duke University, and the Associate Director of Biostatistics at the Duke Clinical Research Institute (DCRI). Dr. Anstrom earned his bachelor’s degree in Statistics and Biometry at Cornell University, his master’s in Biostatistics at University of North Carolina at Chapel Hill, and his doctorate in Statistics from North Carolina State University. Along with Anastasios “Butch” Tsiatis, Dr. Anstrom developed inverse propensity score weighted estimators for average causal effects in randomized and nonrandomized studies. Along with Drs. Michael Felker and Joseph Rogers, he proposed the so-called “Global Rank” endpoint for heart failure Phase II clinical trials. Dr. Anstrom is the author of more than 100 publications with a focus on clinical trials, propensity score methods, outcomes studies, and economic and quality-of-life studies.
Dr. Mark is a clinical cardiologist and Professor of Medicine as well as Vice Chief for Academic Affairs in the Division of Cardiology, Department of Medicine at Duke University Medical Center, where he has been on the full-time faculty since 1985. He is also the Director of Outcomes Research at the Duke Clinical Research Institute. Dr. Mark’s major research interests include economic and quality of life consequences of cardiovascular disease and its therapies, outcomes research, and comparative effectiveness analyses. Currently, Dr. Mark is directing a number of outcomes analyses for ongoing NIH-funded clinical trials including PROMISE, CABANA, ISCHEMIA, GUIDE-IT, and STICHES. He has authored over 305 peer-reviewed articles, two books, and 80 book chapters, and he is Editor of the American Heart Journal.