November 19th, 2013
An Insider’s Look at TACT
Changing minds is difficult. Unexpected results meet resistance. Out of the mainstream research is subject to heavy criticism. I guess I knew all these truisms when we embarked on the Trial to Assess Chelation Therapy (TACT). Still, I thought we were answering an important clinical question.
As a practicing cardiologist, patients still ask me whether they should undergo chelation therapy. A patient asked that question in 1999 and I said “No.” But I was in a scientific mood that week, and decided to look into the literature supporting my answer. There were reams of case reports and case literature, mostly in odd journals I did not read, supporting the practice. But there was no clear-cut randomized trial evidence that would allow me to make a recommendation to my patient. In fact, “no” should have been “I don’t know.” I then thought about the problem for a few weeks and decided that it should yield to a clinical trials approach.
The next step was to make sure that my friend and colleague, Kerry Lee, the senior biostatistician at Duke Clinical Research Institute with whom I have worked since 1995, was on board. In his usual understated way he assured me he was game. And so started a multi-hundred hour, 3-year quest that led to a National Center for Complementary and Alternative Medicine (NCCAM)-NHLBI RFA and an award of $30 million in 2002. An FDA investigational new drug application followed; then approval by multiple committees, the data and safety monitoring board (DSMB), and dozens of institutional review boards (IRBs). The first patient was enrolled a year later in 2003. TACT was underway, enrolling patients in an alliance of conventional cardiologists and chelation practitioners.
To say that this trial was controversial is an understatement. I had previously worked peacefully in other clinical trials, worrying about enrollment, about the DSMB, and about interpretation of data. Not so, here. In retrospect, I had always thought that the adversaries to this study would be the chelation practitioners. After all, they were using an unproven therapy. Why would they want us to show it did not work?
The opposite was true. The chelation practitioners and their main professional organization, the American College for Advancement in Medicine, helped us at every turn. They felt they were doing good, and that bringing chelation to the crucible of a clinical trial would lead to many more patients being helped.
In fact, the principal obstructionists were groups of self-appointed anti-chelation “experts”, who had never administered chelation, had never designed or run clinical trials, but who knew how to make noise and recruit media to their dubious cause – that scientific thought should not be brought to bear on the question of whether chelation was safe and effective. These groups used the Freedom of Information Act to get our protocols, spread hyperbole and twisted facts to recruit journalists, and even persuaded the Office for Human Research Protections (OHRP) to start an investigation.
But in our clinical research world, the truth usually wins. OHRP was thorough and professional. The investigation ended. The IRBs, with a few exceptions, acted ethically, and the acid journalists went on to hector other undeserving targets. We continued to enroll and infuse.
Finally, the study ended after enrolling 1708 patients and administering 55,222 infusions of chelation or placebo. After being blinded for a decade, we finally had the unblinding meeting at Duke in August 2012. By the way, Kerry Lee is like the sphinx. I never had any idea of the results.
We were astonished (our chelation colleagues were not). The study was positive. EDTA chelation reduced events by 18% in an optimally treated post-MI population, and we presented at the AHA Scientific Sessions in 2012.
Uh oh. More knives came out. No, I won’t name names here.
The gist of the objections to the trial, once legitimate methodological concerns were addressed, was an outcry that, because cardiologists believed that EDTA was quackery, the study had to be negative. Therefore we had done something wrong. Just imagine if this had been stem cells or a new anti-platelet: Kudos all the way, right? Humble chelation got heckles and hecklers. I told my dean at Columbia that people were very upset because they did not like the results. He said “That’s why you do research.”
But there are some great scientists and editors out there. The JAMA editors were superb. Their criticism was tough, but they believe in the scientific process. The NHLBI and NCCAM scientists, likewise – they are interested in the process leading to a valid answer, no matter what that is. The editor of Circulation: Cardiovascular Quality and Outcomes is also a scientist who is not afraid of unexpected results. So where are we today? What are the take-home points after this AHA 2013?
1. First of all, be happy that this is a non-guideline message.
2. In a population of well-treated post-MI patients, age 50 or older, treatment with an EDTA-based regimen is safe and leads to a modest reduction in combined cardiovascular endpoints.
3. The benefit of the EDTA-based regimen is made about 10% greater by the inclusion of very high-dose oral multivitamins and multiminerals.
4. Diabetic patients derive a greater benefit from EDTA chelation than do non-diabetics. They demonstrated a 41% reduction in combined cardiovascular events, including a 43% reduction in total mortality and a 50% reduction in recurrent MI. There is nothing like this in diabetes.
So now what? Do we recommend chelation? This is where the cautious scientist has to take control. We reported a subgroup, and we have been fooled by subgroups before, so more research has to take place before all of us can jump on this bandwagon.
There are scientific messages that have been ignored while the anti-chelation outcry was loudest, however.
1. There is sound epidemiologic evidence that metals are associated with cardiovascular disease.
2. Advanced glycation end products, mediators of complications of diabetes, almost all require auto-catalytic metal chemistry for their oxidation and cross-linking.
3. Metals also poison our intrinsic mechanisms to detoxify reactive oxygen species.
4. Therefore, anti-oxidant effect is our leading hypothesis.
So the findings have some mechanistic legs, but none that, at present, we can prove. My hopes are that we can pull together as a scientific community, and through the NIH, investigate these striking findings to get a new handle on treating the vascular complications of diabetes. As I said above, there is nothing else like this out there for our diabetic patients.