EBM Tools for Practice: Chelation Therapy is a Proven Treatment for Cardiovascular Disease: Myth or Fact?

Cardiovascular disease (CVD) is the leading cause of death in the U.S.1 There have been many important advances in the treatment of CVD in recent decades. However, not all touted therapies carry the same quality of evidence supporting their use. Chelation therapy is one such treatment that has been controversial since its inception more than half a century ago. Is its use as a treatment for CVD proven or a myth?

Chelation therapy, the intravenous infusion of ethylenediaminetetraacetic acid (EDTA), was first recognized as a treatment for lead toxicity in the 1950s.2  Later that decade, Clarke and colleagues made the association between EDTA and the dissolution of metastatic calcium when a patient with nephrocalcinosis treated with EDTA had radiographic improvement in kidney stone burden.3  This observation, coupled with observations that calcium and cholesterol are components of atherosclerotic plaques, led investigators to hypothesize that EDTA chelation therapy could dissolve calcium- forming plaques and, therefore, treat cardiovascular disease.4,5

In subsequent years, two controlled clinical trials were conducted to look at this question, but each found no difference between placebo and EDTA therapy for the treatment of CVD.6,7  This is in contrast to many case reports and three open-label studies, which described improvement in the signs and symptoms of CVD.5,8,9 In addition, there was one meta-analysis of uncontrolled trials and unpublished data that concluded chelation therapy was effective at improving CVD symptoms in more than 80 percent of cases.10 These positive studies were criticized for their small sample sizes, open-label designs, and the use of qualitative, rather than quantitative, endpoints.5

More recently, there have been multiple systematic reviews of the literature on this topic. A literature review by Grier and Meyers looked at 16 case reports or case series, two longitudinal studies, three clinical trials, and 19 book testimonials.11

The authors concluded that there was little valid scientific evidence to support the use of chelation therapy for the treatment of CVD. Moreover, they believed that the best evidence showed it to be ineffective.11

A systematic review by Villarruz and colleagues analyzed five randomized, controlled trials of EDTA chelation therapy in patients with atherosclerotic CVD. The authors found that four of the five studies showed no significant difference in direct or indirect measurement of disease severity and subjective measures of improvement.12

They concluded that there was insufficient evidence to decide on the effectiveness of chelation therapy based on the available evidence.12 Three other systematic reviews of clinical trials concluded that chelation therapy is not supported by evidence.13-15

Despite the paucity of evidence for EDTA therapy and its as yet undefined risks, chelation therapy grew in popularity, from 66,000 treatments in 2002 to 110,000 in 2007.16  Treatments cost between $75 and $125 per session, and most patients undergo dozens of treatments over several months.17 Therefore, one complete treatment course can cost in excess of $5,000.17  Most often, patients incur the full cost of treatment, as health insurance typically does not cover EDTA therapy.17 Nationally, the estimated out- of-pocket costs for EDTA to treat CVD ranges from $400 million to $3 billion.18,19

For these reasons, in 2003, the National Heart, Lung and Blood Institute and the National Center for Complementary and Alternative Medicine sponsored the Trial to Assess Chelation Therapy (TACT).20 This multicenter clinical trial of 1,708 patients with previous myocardial infarction (MI) were randomized to receive 40 infusions of chelation solution or placebo. After a median follow up of 55 months, the primary endpoint (total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred in 222 (26 percent) patients in the chelation group and 261 (30 percent) patients in the placebo group with a P value of 0.035.20  The most significant between- group difference involved fewer coronary revascularizations in the chelation group (15 percent) than in the placebo group (18 percent).20 The authors conclude that, among patients with a history of MI, the use of chelation therapy modestly reduced the risk of adverse cardiovascular outcomes. They go on to say that the results are not sufficient to support the routine use of chelation therapy for this patient population.20

From the outset, this study was met with controversy. There were concerns over the credentials and capabilities of the study clinical sites. Many were described as complementary and alternative medicine clinics known to offer a variety of unproven therapies to patients, perhaps undermining their ability to perform a high-quality study.21 Ethical issues also arose around the informed consent process for study participants, resulting in an investigation by the Office for Human Research Protections.22,23 Additionally, there were multiple concerns with the fundamental study design and implementation.21,22 For example, 18 percent of the original study population was lost to follow-up, with significantly more patients withdrawing from the placebo group than the chelation group.20 This unexpected finding has led some to believe that there was unmasking of treatment assignments.21 Another frequently cited limitation of the trial was its use of two less objective and reliable endpoints — coronary revascularization and hospitalization from angina — in the primary composite outcome.21

Taken together, the evidence for chelation therapy as a treatment for CVD, from the 1950s through present day, is inconclusive at best. The majority of studies conducted with scientific rigor have concluded that chelation therapy is not supported by evidence and many of the studies supporting the treatment are fraught with criticisms. Indeed, the Journal of the American Medical Association editors conclude that the TACT trial findings do not support the routine use of chelation therapy as secondary prevention for patients with MI.22 Chelation therapy has long been controversial, but given the current state of the evidence, the myth is busted that chelation therapy is a proven treatment for CVD.

Disclosure statement: Dr. Kelly has no disclosures to report. Dr. Hemphill received a clinical research grant as a principal investigator from Regeneron/Sanofi and Ionis Pharmaceuticals. She received honorarium from Aegerion.

References are listed on page 35 of the PDF.