Published: Mar 26, 2013
By Chris Kaiser , Cardiology Editor, MedPage Today

Action Points

• Note that this troubled randomized trial showed a modest benefit to chelation therapy in secondary prevention after myocardial infarction.
• Be aware that greater dropout in the placebo group suggests unblinding of the intervention.
• Note that many sites participating in the trial had little experience with clinical trials and offered unproven therapies.

Results of the troubled TACT randomized clinical trial do not support the routine application of chelation therapy in patients with a previous heart attack, researchers found.

Only a modest effect was seen for chelation therapy to reduce the risk of cardiovascular events in patients with a previous heart attack, according to Gervasio A. Lamas, MD, of Mount Sinai Medical Center in Miami Beach, and colleagues. Those in the intervention group had an 18% lower risk of reaching the primary endpoint — a composite of total mortality, recurrent myocardial infarction (MI), stroke, coronary revascularization, or hospitalization for angina (HR 0.82, 95% CI 0.69 to 0.99, P=0.035).

“The significance threshold required at the final analysis was P=0.036,” and in light of the confidence interval just barely reaching statistical significance, the controversial therapy is not yet ready for routine clinical practice, they wrote in the March 27 issue of the Journal of the American Medical Association.

Chelation therapy is an intravenous administration of chelating agents (such as disodium ethylene diamine tetraacetic acid [EDTA], which was used in this study) to treat heavy-metal toxicity. Through the years, anecdotal accounts and case reports have praised the therapy for its healing powers, but small clinical trials have not found any benefit – measured by surrogate endpoints — associated with chelation, and the CDC has reported cases of harm associated with the therapy.

In this study, the primary endpoint occurred in only 39 fewer patients in the chelation treatment group compared with the control group, and if only a few more patients had reached the primary endpoint, the outcome would not have been significant at all, commented Steven Nissen, MD, from the Cleveland Clinic, in an accompanying editorial.

Nissen also pointed to the 18% of patients lost to follow-up as one of the problems of the study, with the high rate possibly a result of having “questionable” centers involved. Many of the centers, he noted, offered a myriad of “unproven therapies ranging from stem cell therapy to regrow breasts after mastectomy … to the use of cinnamon for treating diabetes.”

In addition, such a high dropout rate suggests unmasking, Nissen said, adding that “intentional unblinding” by the sponsor — the National Institutes of Health — “is more concerning” than the possible unmasking. Apparently, NIH policy “unwisely allows the sponsor access to unblinded trial data,” which is not in line with acceptable standards for supervising clinical data.

With these and other problems of the trial, Nissen concluded that “the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy.”

Silver Lining?

Some hints of potential benefit from chelation therapy did appear in two prespecified subgroups, however. Patients with diabetes had a 39% reduced risk of the primary endpoint (HR 0.61, 95% CI 0.45 to 0.83, P=0.02). Similarly, patients with anterior MIs had a 37% reduced risk (HR 0.63, 95% CI 0.47 to 0.86, P=0.03). The authors pointed out that site investigators were responsible for identifying the location of the infarction.

“Both of these subgroups were prespecified based on representing important high-risk subsets of patients, but not because there was any specific biologic reason for suspecting that chelation would be uniquely beneficial for these patients,” Lamas and colleagues said. More research is needed to determine if this finding can be replicated, they added.

The study is a 10-year, $31 million, NIH-funded effort entitled TACT (Trial to Assess Chelation Therapy). It was supposed to put an end to the controversy that surrounds chelation, but instead it seems to have raised the level of dispute even more.

In fact, when the study was presented at the American Heart Association’s meeting in November, a representative from the AHA felt the need to read an AHA-endorsed statement at a press briefing that said, in part, “intriguing as the results are, they are unexpected and should not be interpreted as an indication to adopt chelation therapy into clinical practice.”

The person reading the statement was Elliott Antman, MD, of Harvard Medical School in Boston and a past president of AHA, who said he wanted to have the statement on record since the press briefing was being recorded.

But it’s not just the modest effect chelation therapy had on the primary endpoint that is controversial. The study also has been plagued by many issues since its inception, Howard Bauchner, MD, editor-in-chief of JAMA, and two editorial colleagues wrote in an accompanying commentary. The concerns that arose 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 investigators
• Temporary suspension of trial enrollment
• Safety of the chelating agent
• Modification of the prespecified sample size and alteration of the prespecified statistical significance levels because of multiple interim analyses

Bauchner and colleagues also noted how thoroughly the TACT study was scrutinized and reviewed, and how Lamas and colleagues “thoroughly and directly” addressed the “extensive critiques and concerns” raised by the reviewers.

Ultimately, the decision to publish the study, despite its limitations and controversy, centered on several points, Bauchner and colleagues wrote, including to help generate novel hypotheses, to understand the small benefit of chelation as a secondary preventive measure in those with cardiovascular disease, to understand the many important study limitations, as a courtesy to the investigators who had the persistence to see the study to its end, and as a courtesy to the patients.

For his part, Nissen noted that Lamas and colleagues “fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate.”

However, in agreement with Bauchner and colleagues, Nissen said that all randomized controlled trials should be published, since “even failed trials provide valuable scientific lessons for the medical community,” such as the “overwhelming challenges” of assessing the effectiveness of a controversial therapy.

Study Design

For the study, Lamas and colleagues enrolled 1,708 patients 50 years of age or older (median age 65) who had experienced an MI at least 6 weeks prior (median 4.6 years before enrollment). Participants were recruited at 134 U.S. and Canadian sites.

The treatment group received 40 infusions of a 500-mL chelation solution (3 g of EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) and an oral vitamin-mineral regimen. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart.

Researchers noted as a limitation the unblinding as a possible explanation for more withdrawals in the placebo group. Other limitations were a challenging treatment regimen for patients, not having an explanation of the mechanism by which chelation therapy works, and the use of a composite endpoint, particularly one that includes the “soft” endpoint of revascularization.

From the American Heart Association:

• AHA Science News from Sessions 2012: TACT

Primary source: Journal of the American Medical Association

Full Story:  http://www.medpagetoday.com/Cardiology/Prevention/38095