Results of the troubled TACT trial were published March 27 in the Journal of the American Medical Association, a move made even more controversial with the inclusion of two accompanying editorials. But all authors agreed on one point: Routine use of chelation therapy, the focus of the trial, as a treatment for patients who experienced an MI, is not warranted.
TACT (Trial to Assess Chelation Therapy) is a $31 million multicenter clinical trial that was funded by the National Institutes of Health to determine if use of the drug disodium EDTA reduced cardiovascular events in patients with a prior MI. The trial was launched in response to what lead author Gervasio A. Lamas, MD, of Mount Sinai Medical Center in Miami Beach and colleagues described as “the public health problem posed by EDTA chelation therapy: large numbers of patients being exposed to undefined risks for unproven benefits.” In particular, chelation advocates increasingly were using disodium EDTA as a treatment for coronary and peripheral artery disease.
The double-blind, placebo controlled trial enrolled 1,708 patients who experienced an MI at least six weeks before enrollment and assigned them to receive either infusions of a chelation infusion or placebo. Patients received three-hour infusions weekly for the first 30 weeks and then 10 more infusions two to eight weeks apart. The primary endpoint was the composite of death from any cause, reinfarction, stroke, coronary revascularization or hospitalization for angina.
But the trial, which initiated enrollment in September of 2003, encountered several hurdles.
- It originally aimed to enroll 2,372 patients over three years for a minimum one-year follow-up, which was reduced to 1,700 in 2009 due to slow enrollment; the trial closed in October 2011;
- The data and safety monitoring board requested 11 interim analyses;
- Only 65 percent of enrollees completed 40 infusions and 76 percent completed at least 30;
- 28 percent discontinued infusions in the chelation group and 32 percent in the placebo group; and
- 17 percent of the patients withdrew consent for continued follow-up.
Lamas et al found 40 infusions of chelation therapy led to a small reduction in the composite outcome, with an occurrence rate of 26 percent in the chelation group and 30 percent in the placebo group. They conducted sensitivity analyses to address patient withdrawal and loss to follow-up and determined that the results, albeit modest, held up.
“[T]he necessity of using a composite endpoint as the primary outcome event in a clinical trial creates some unavoidable uncertainties about the actual treatment benefit because study power is insufficient to show an effect on any individual endpoint and the components are not all considered of equal clinical importance,” they wrote.
Beside the problems associated with the high number of patients who withdrew consent, they wrote that unblinding might have led to patients discontinuing therapy, although they considered widespread unblinding as unlikely. They also acknowledged that the three-hour infusion period might have been a burden for patients.
The findings might be due to chance, given “the narrow difference between the significance level calculated and that prespecified for the analysis. Accordingly, the results of this study should be viewed as an important but single step on the long path toward better understanding the pathophysiologic and therapeutic implications of chelation therapy but do not provide evidence to support its routine use in clinical practice,” they concluded.
JAMA editors Howard Bauchner, MD, Phil B. Fontanarosa, MD, MBA, Robert M. Golub, MD, provided an accompanying editorial that detailed extra steps taken in reviewing the TACT study. They outlined past controversies, including ethical issues raised by the Office for Human Research Protections (OHRP), questions about the credentials of study site and site investigators, enrollment issues, safety concerns and alterations after the numerous interim analyses. Besides evaluating the study manuscript, they looked at OHRP reports and other documents. The manuscript also went through peer review and revisions.
“This evidence and information should serve to dissuade responsible practitioners from providing or recommending chelation therapy for patients with coronary disease and should discourage patients with previous MI from seeking this therapy with the hope of preventing subsequent cardiovascular events,” the editors wrote.
Cleveland Clinic’s Steven E. Nissen, MD, focused on the study’s limitations in a second editorial, arguing that TACT illustrates how a clinical trial’s shortcomings can compromise its results and value. He took exception with the use of study facilities described as “complementary and alternative medicine sites.”
“A common theme of these centers is evident—they appear to attempt to appeal to vulnerable patients who have challenging diseases by offering a variety of unscientific and unproven therapies,” Nissen wrote. “Whether a high-quality RCT [randomized controlled trial] can be performed at such sites is questionable.”
He pointed out that the placebo group experienced a higher number of withdrawn consents and discontinuation of the infusions. “The occurrence of the primary endpoint in just a few more patients in the chelation treatment group would yield a statistically nonsignificant result. ... No imputation strategy can successfully recover missing outcome data when the missing data are unequally distributed between treatment groups and the treatment benefit is barely statistically significant.”
Unblinding of NIH sponsors also compromised the study because it gave them access to data during interim analyses, despite their investment, he argued.
“[T]he results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy,” Nissen wrote. “The findings of TACT should not be used as a justification for increased use of this controversial therapy.”