A TACT-ful discussion

Integrative medicine

In January 2013, this column discussed the preliminary findings of the Trial to Assess Chelation Therapy (TACT) based on information presented at the annual meeting of the American Heart Association (AHA). The study has now been published, and the debate regarding its findings shows no signs of stopping.1,2

TACT’s objective was to determine if an ethylene diamine tetra-acetic acid (EDTA) chelation regimen of 40 infusions decreased the risk of cardiovascular events in patients who had a prior myocardial infarction (MI) and who were receiving standard evidence-based post-MI care. The primary endpoint was a composite of death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina. A secondary endpoint was the composite of cardiovascular death, reinfarction, or stroke. TACT investigators enrolled a total of 1,708 patients with a median follow-up of 55 months. The study population consisted primarily of white men with a median age of 65 years; 31% of patients had diabetes. Participating sites included chelation centers (60%) as well as standard medical centers.1

The primary endpoint was reached in 26% and 30% of patients in the chelation and placebo groups, respectively. Coronary revascularization contributed 45% of the primary endpoint events and drove the apparent difference between the two groups. Researchers identified a greater benefit in two prespecified subgroups: patients with diabetes and those with anterior wall MI, although the reasons for this finding are not known. The outcomes did not vary based on whether the site was a chelation center or a standard medical center site. Hypocalcemia was the most serious adverse effect and occurred more commonly with chelation therapy.1

Criticism

TACT has attracted controversy in part due to the lack of an established scientific rationale for the efficacy of chelation. FDA had raised concerns about the conduct of the study at some complementary and alternative medicine sites, but these were later addressed to the agency’s satisfaction. Some chelation centers involved in the study promoted very controversial alternative therapies on their websites, which critics contended raised concerns about their commitment to an unbiased evaluation of the therapy. The chelation infusions were also criticized, but researchers selected the infusions for their similarity to those used routinely in practice and the placebo to match as closely as possible.

Investigators were unable to recruit the target population of 2,400 people and, as a result, extended the follow-up period to maintain the power of the study. Critics have also objected to the components of the primary endpoint, noting that coronary revascularization is a “softer” outcome that can be at the discretion of the physician. The components are typical of many cardiovascular studies, however.

Another issue with TACT was access to unblinded data by sponsors and investigators during the study; the authors have denied having access. Eleven interim analyses were performed during the course of the study, which is quite unusual.1,2 Finally, withdrawal of consent occurred more frequently in the placebo group. In response to this issue and at the request of JAMA editors, the authors performed multiple analyses to evaluate the potential effects of dropouts and withdrawals on the primary endpoint.3

Fallout

After the AHA meeting last November, some critics argued that the completed TACT manuscript should never be published, especially in a major medical journal. These parties pointed to the significant concerns about the study methodology and the fact that any slight benefit from chelation could be used to further promote a still unproven therapy, at the expense of established approaches.

Although these concerns are legitimate, drug therapies are routinely promoted based on minor benefits from published studies. The scientific review process, as described in the accompanying JAMA editorial, should be rigorous enough to permit an open and informed discussion of all evidence.2,3

In summary, health professionals should interpret TACT as a largely negative study of a commonly administered alternative treatment for cardiovascular disease that may possess significant adverse effects.

References

  1. Lamas GA, Goertz C, Boineau R et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction. JAMA. 2013;309:1241–50.
  2. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. 2013;309:1293–4.
  3. Bauchner H, Fontanarosa PB, Golub RM. Evaluation of the trial to assess chelation therapy. The scientific process, peer review, and editorial scrutiny. JAMA. 2013;309:1291–2.