Controversial study finds little benefit from chelation

Chelation therapy, a 1950s treatment for lead poisoning that has become an increasingly popular alternative medicine treatment for conditions as diverse as autism and heart disease, received a lukewarm endorsement from a government-funded clinical trial that is drawing criticism for its methods and the possibility of investigator bias.

The results of a controversial 10-year, $31 million, National Institutes of Health-funded study, published in this week's Journal of the American Medical Association, showed a small reduction in the risk for subsequent cardiac events in patients receiving chelation therapy after a heart attack. An accompanying editorial by Dr. Steven Nissen of the Cleveland Clinic criticized the study for its high dropout rate, changing of trial design midway through the study, its missing data, investigator biases and the intentional unblinding of the sponsor.

Chelation therapy involves infusion of ethylene diamine tetraacetic acid, or EDTA, to promote the removal of substances such as lead, cadmium, calcium and aluminum from the body and into the urine. Ethical complications of the study included the potential risk of abnormally low calcium levels in the blood and a scientific consideration included the high number of participants who withdrew from the trial.

In September 2003, 1,708 participants who had previously had a heart attack were enrolled in the trial (mostly overweight, white men older than 65), with 839 getting infusions of disodium EDTA along with oral doses of vitamins and minerals and 869 receiving placebos. Followup took place in October 2011. But by that time, 289 patients (17%) had withdrawn their consent to participate in the trial. Also, 22 patients were “lost” and did not participate in the followup. In addition, there were 233 patients who discontinued the infusion regimen (38 because of an adverse event) and 281 who discontinued the placebo regimen (41 because of an adverse event).

Overall, the number of cardiac events was lower among the infusion group. They suffered 52 heart attacks compared to 67 in the placebo group; 10 strokes compared to 13 in the placebo group; 130 required procedures to restore blood flow to the heart compared to 157 in the placebo group; and 13 were hospitalized for angina or chest pain compared to 18 in the placebo group. The authors stated that the study was “not powered to compare death rates,” but went on to list that 87 infusion patients died (50 having a “cardiovascular death”) and 93 placebo patients died (51 having a cardiovascular death).

“These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI,” the authors concluded.

In his editorial, Nissen said it was right for JAMA to publish the results. The “investigators fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate,” he said. “Nonetheless, all RCTs (random controlled trials) should be published because even failed trials provide valuable scientific lessons for the medical community … (The) TACT (Trial to Assess Chelation Therapy) provides useful insights into the overwhelming challenges faced when trying to determine the effectiveness of an unusual and controversial therapy.”

In another editorial, Dr. Howard Bauchner, JAMA's editor-in-chief, and two other physicians, noted concerns over patient safety, modification of the sample size and alteration of “prespecified statistical significance levels.” But he said the manuscript was extensively reviewed and that the authors' responses to concerns were “scholarly and thorough.” Bauchner and colleagues also wrote that the NIH-sponsored study had passed institutional review board scrutiny, and noted that—despite setbacks and criticism—the researchers “demonstrated courage and persistence in continuing this trial to its completion.”

“The study has generated controversy since its inception, with concerns that have included ethical issues involving an investigation by the Office for Human Research Protections regarding allegations of noncompliance with federal regulations for the protection of research participants; study conduct issues involving allegations about the research capabilities and professional credentials of some study sites and site investigators, as well as temporary suspension of trial enrollment; and fundamental scientific issues, involving concerns ranging from the safety of the chelating agent being studied to modification of the prespecified sample size,” they wrote.

Though, in the end, these authors merely concluded that “Whether chelation therapy may have any role in the prevention and treatment of cardiovascular disease remains to be determined.”

JAMA has published studies on the efficacy of alternative treatments before, but the patient-safety stakes may not have been as high. These included reports on the efficacy of herbal remedies, such as using echinacea to treat children's respiratory infections, the effect of ginseng supplements on anti-clotting drugs, and the use of ginko biloba to prevent cognitive decline in adults.