TACT Published: Controversial Study Under Scrutiny in JAMA

March 26, 2013

MIAMI — The Trial to Assess Chelation Therapy (TACT), a 10-year, $31-million study funded by the National Institutes of Health (NIH), is now published in the Journal of the American Medical Association (JAMA), and while the results have been reported extensively by heartwire and other media outlets, the decision to publish the trial was based on a comprehensive editorial assessment by the JAMA editors[1].

"Because articles published in journals like JAMA can influence the practice of medicine, this level of scrutiny of TACT reflects our commitment to fulfilling the responsibility to try to ensure that every article published in JAMA is valid and is reported accurately," write editor-in-chief Dr Howard Bauchner, executive editor Dr Phil Fontanarosa, and deputy editor Dr Robert Golub in a March 26, 2013 letter accompanying the published trial[2].

TACT, a positive, if perplexing, study, suggested that chelation therapy may modestly improve clinical outcomes in patients after an acute MI. Over a four-year follow-up, those who followed an arduous regimen involving up to 40 separate three-hour infusions of a standard chelation-therapy solution of multiple ingredients, compared with a placebo, showed an 18% drop in the trial's primary end point. Adverse effects were mostly minimal.

However, as the JAMA editors point out, the study attracted controversy with concerns that included ethical issues involving an investigation by the Office for Human Research Protections (OHRP) because of allegations of noncompliance with federal regulations for the protection of research participants. Other issues that arose included allegations about the research capabilities and professional credentials of some study sites and investigators, concerns about the safety of the chelation agent, modification of the prespecified sample size, and a change in the prespecified statistical-significance levels because of multiple interim analyses.

Back in 2003, when this trial was announced, I thought it was a crazy notion.

Given these concerns, as well as the recognition that the "publication of research reports in influential journals can do harm," the editorial assessment of TACT went beyond assessing the scientific validity and clinical relevance of the trial, according to the JAMA editors.

"Accordingly, the editorial review and scientific assessment involved not only JAMA’s usual level of scrutiny and diligence in evaluating the research report, including careful review of the study protocols, statistical analysis plans, and methods papers--it also involved assessment of OHRP reports, other documents related to the ethical and regulatory aspects of trial conduct, and reports of professional and public reaction about the study," write Bauchner, Fontanarosa, and Golub.

The TACT Data

Led by Dr Gervasio A Lamas (Mount Sinai Medical Center, Miami Beach, FL), TACT has been controversial in its long history. As reported byheartwire , ethics questions had been raised about the quality of disclosure to patients about possible treatment effects and criticisms leveled at a perceived waste of public money. Enrollment had been slow, and it was stopped and restarted a number of times.

Against the odds, however, the trial was completed and presented at the American Heart Association 2012 Scientific Sessions in Los Angeles, CA. The hazard ratio for the primary composite end point for chelation therapy vs placebo, by intention to treat, was 0.82 (95% CI 0.69–0.99; p=0.035). There were no significant differences in the individual components of the primary end point, but all trended in favor of chelation therapy.

Dr Eric Topol (Scripps Clinic, La Jolla, CA) called TACT one of the "most controversial trials that has been published in cardiovascular medicine in a long time." Like others, Topol said TACT is a trial with a lot of "warts," among them the 18% of patients lost to follow-up and the imbalance in the number of patients who withdrew from the study (174 patients in the placebo arm vs 115 in the chelation-therapy arm; p=0.001).

"But what is notable about this trial is the consistent directionality of the end points," said Topol in a video blog available on theheart.org. "There was an overall 18% reduction in a composite end point, which included death, heart attack, stroke, coronary revascularization, and hospitalization for angina, but each of these was reduced." Subgroup analyses also revealed that patients with diabetes and those with an anterior MI also appeared to benefit significantly from chelation therapy, said Topol.

Positive Study, But Do Not Undergo Chelation Therapy, Say Docs

In an editorial accompanying TACT[3], Dr Steven Nissen (Cleveland Clinic, OH) said TACT highlights the overwhelming challenges when conducting a trial involving a controversial treatment. Nissen also pointed to some of the trial's flaws, noting that the sponsors of the study, including the National Heart, Lung, and Blood Institute (NHLBI) and National Center for Complementary and Alternative Medicine (NCCAM), were unblinded throughout the trial. This gave them access to confidential data during each of the 11 interim analyses.

"The unblinding of the study sponsor represents a serious deviation from acceptable standards of conduct for supervision of clinical trials. If a pharmaceutical company sponsoring a trial were allowed access to actual outcome data during the study, there would be major objections," writes Nissen. "Like any sponsor, the NHLBI and NCCAM cannot be considered unbiased observers. These agencies made major financial commitments to the trial and may intentionally or inadvertently influence study conduct if inappropriately unblinded during the study."

In addition to these concerns, Nissen said that the occurrence of the primary end point in just a few more patients in the placebo arm would have turned the trial into a negative study. He points out that 318 of the 483 total events that made up the primary end point were composed of soft end points, such as coronary revascularization and hospitalization for angina. If unblinding occurred, investigator biases could influence the decision to hospitalize or revascularize patients, according to Nissen.

But what is notable about this trial is the consistent directionality of the end points.

"Given the numerous concerns with this expensive, federally funded clinical trial, including missing data, potential investigator or patient unmasking, use of subjective end points, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy," concludes the editorialist. "The findings of TACT should not be used as a justification for increased use of this controversial therapy."

Even the TACT researchers don't recommend the routine use of chelation therapy in post-MI patients, stating in JAMA that the results should only be used to guide future research.

For Topol, he said the data are at least reassuring because he has had many patients in the clinic who have undergone or are undergoing chelation therapy as an alternative treatment for their heart disease. In the past, he was concerned that such treatment was harming them, but at least TACT reassures on that front. "And when you look at the data, it looks like there is something going on," he added. Importantly, Topol sees a little light in the publication, namely that the study challenges the existing dogma regarding chelation therapy, although he too does not recommend the treatment to patients.

"Back in 2003, when this trial was announced, I thought it was a crazy notion," said Topol. "At the end of the day, after all this work of all these investigators, I give them credit, and I give the JAMA editors credit for publishing it. It will be controversial and it will be provocative, but that's a good thing for a clinical trial."

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