Is Chelation Therapy Finally Here to Stay?

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationships relevant to this field of study.

Synopsis: Use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes in stable patients with a history of myocardial infarction (MI). These results do not support the routine use of chelation therapy for treatment of patients who have had a prior MI.

Source: Lamas GA, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: The TACT randomized trial. JAMA 2013;309:1241-1250.

Treatment of encephalopathy caused by lead toxicity with chelation using disodium (EDTA) was first reported in 1952;1 however, it wasn’t until 1956 that chelation was used to treat patients with angina pectoris2 and other atherosclerotic illnesses.3-5 Over the years, the numbers of patients using chelation therapy had increased dramatically,6 and soon large numbers of patients were being treated and being exposed to undefined risks for benefits that have remained, for the most part, unproven. As a result, the National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Complementary and Alternative Medicine (NCCAM) provided sponsorship and oversight for a trial using an FDA investigational new drug application for intravenous disodium EDTA for the treatment of coronary artery disease (CAD).

The Trial to Assess Chelation Therapy (TACT) was a double-blind, placebo-controlled, 2 × 2 factorial randomized trial conducted at 134 U.S. and Canadian sites. Chelation therapy was already being practiced in 60% of the selected sites. All patients had previously suffered a myocardial infarction (MI) and were randomized to receive either 40 intravenous infusions of disodium EDTA chelation solution combined with an oral vitamin-mineral regimen vs a placebo infusion and an oral placebo. The primary endpoint was a composition of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. The results demonstrated that chelation therapy modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures.7

Commentary

Chelation therapy for the treatment of patients with CAD has been controversial since its introduction in the early 1950s and, even after the results of this NHLBI/NCCAM-sponsored study were published,7 it remains controversial. Despite being a double-blind, placebo-controlled trial that demonstrated a modest reduction in the risk of adverse cardiovascular outcomes, the authors noted numerous limitations of the TACT trial. They noted multiple concerns, including: 1) the necessity of using a composite endpoint as the primary outcome event in a clinical trial, 2) concern about the unusually high number of patients withdrawals, 3) “un-blinding” of the study results which occurred during the course of the trial, and 4) the difficulty endured by patients because of the need to receive 40 infusions each lasting 3 hours. In one of the editorials in the same JAMA issue, Dr. Steven Nissen noted that more than 60% of the patients were randomized at centers described as complementary and alternative medicine sites and he appropriately raised a concern as to whether all of the sites were adequately populated by the skilled investigators and study coordinators (i.e., the lack of which may have contributed to the relatively high patient dropout rate) needed to conduct a randomized, controlled trial.8 A second editorial in JAMA by Bauchner and colleagues noted that the study had generated controversy since its inception and “despite numerous setbacks, criticisms and concerns, the funding agencies and the investigators (who include one of the preeminent cardiovascular researchers and one of the most respected statisticians) demonstrated courage and persistence in continuing this trial to its completion.”9

In summary, despite all concerns about the reliability of its results, the quite expensive, federally funded TACT trial demonstrated that chelation therapy modestly reduced the risk of composite adverse cardiovascular outcomes.7 However, the benefits (if there are any at all) are small, and it is important to recognize the many important study limitations (i.e., marginal statistical significance of the main finding, relatively high dropout rate, and the potential alteration of the study results by unmasking). In my opinion, the findings of the TACT study do not support the routine use of chelation therapy as secondary prevention for patients with prior MIs and/or established CAD. At most, the results do provide some support to recommend additional research studies. However, as has been clearly demonstrated by the TACT trial, any additional research studies will be expensive and extremely difficult to perform and, even if the results proved to be beneficial, it will be extremely difficult to encourage patients to partake in this very arduous therapy unless there are no other good options for the prevention and/or treatment of CAD, which of course, we all know not to be true at this time.

References

1. Bessman SP, et al. Treatment of lead encephalopathy with calcium disodium versenate; report of a case. Med Ann Dist Columbia 1952;21:312-315.

2. Clarke CN, et al. Treatment of angina pectoris with disodium ethylene diamine tetra acetic acid. Am J Med Sci 1956;232:654-666.

3. Casdorph HR, et al. EDTA chelation therapy: Efficacy in arteriosclerotic heart disease. J Holistic Med 1981;3:53.

4. Cranton EM, ed. A textbook on EDTA chelation therapy. Newburyport, MA: Hampton Roads Publishing; 2001;2:503-539.

5. Guldager B, et al. EDTA treatment of intermittent claudication — a double-blind, placebo-controlled study. J Intern Med 1992;231:261-267.

6. Barnes PM, et al. Complementary and alternative medicine use among adults and children. United States, 2007. Natl Health Stat Report 2008;12:1-23.

7. Lamas GA, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction. JAMA 2013;309:1241-1250.

8. Nissen SE. Concerns about reliability in the trial to assess chelation therapy (TACT). JAMA 2013;309:1293-1294.

9. Bauchner H, et al. Evaluation of the trial to assess chelation therapy (TACT). The scientific process, peer-review, and editorial scrutiny. JAMA 2013;309:1291-1292.