Diabetes affects more than 24 million Americans. It's a terrible disease that more than doubles the risk of vascular death. Any therapy that safely improves outcomes of this increasing prevalent disease has enormous potential to improve public health. These statements are inviolate, regardless of one's preconceived biases or amnesia of medical history.
Yesterday, at the American Heart Association 2013 Scientific Sessions , Dr Esteban Escolar (Mount Sinai Medical Center, Miami Beach, FL) presented a substudy of the previously published and controversial TACT trial. Using a cohort of 633 patients with diabetes, the research team found that chelation therapy substantially lowered the risk of an adverse vascular outcome. The results are compelling, consistent, and vetted. (See comprehensive coverage on heartwire .)
Based on this analysis of TACT, only six patients with diabetes had to be treated with chelation to prevent one adverse outcome. That's less than half the NNT when statins are used in patients with diabetes and established vascular disease—an uncontroversial indication.
Yet the medical establishment is overcome with doubt.
I had a chance to sit down for coffee with TACT principal investigator Dr Gervasio Lamas (Mount Sinai Medical Center, Miami Beach, FL) after his session yesterday. What follows was almost entirely written before our conversation. I left our meeting with a twinge of optimism for the medical establishment.
Where does one even start with the chelation story? I'm a kid at heart, so my mind—not yet burdened with accumulated heavy metals—drifts back to the playground.
I learned as a boy that a game works only when players abide by the rules set out before the game starts. Changing rules in the middle of the game is strictly forbidden. It has to do with integrity.
The medical establishment, the "anointed" if you will, have set out the rules of medicine. We shall use science as our guide to treat fellow humankind. These days, nothing has become more virtuous than evidence-based practice.
Science, however, in its search for truth, can get messy. Humans do that to things. Preconceived notions are strong, conflicts abound, and of course there is the matter of hubris—a doctor's greatest foe. One of the doctors whom I hold in highest regard sent this to me in relation to the establishment:
The machine depends on people being sick to function. If people take control of their own health, the machine falls apart. And it is a billion-dollar business. Who wouldn't aggressively denounce anything that threatens it?
The disruption wrought by the new cholesterol guidelines pales in comparison to the angst surrounding chelation therapy.
Some history. Recall that TACT is a $31-million trial sponsored by the National Center for Complementary and Alternative Medicine (NCCAM) and the National Institutes of Health (NIH). It was a prospective, randomized, blinded trial of chelation therapy vs placebo for the prevention of cardiovascular disease in 1708 high-risk patients. The overall results of the TACT trial were published earlier this year in the prestigious Journal of the American Medical Association. Chelation therapy reduced the risk of the trial primary end point—a composite of death, MI, stroke, coronary revascularization, or hospitalization for angina.
The criticism from the establishment was massive. Anyone who expressed anything less than disdain for this popular complementary and alternative therapy was brought to task. The machine roared.
Here are some thoughts on the criticisms of TACT.
The implausible-theory argument. Critics can conceive of no plausible reason that chelation therapy could treat atherosclerosis. Yet, if "experts" unlocked their minds, they may have happened onto epidemiologic evidence that heavy metals associate with heart disease. Or that glycation end products, mediators of complications of diabetes, mostly require autocatalytic metal chemistry for their oxidation. Or that metals impair our ability to detoxify reactive-oxygen species. Dr Lamas reminded me that most experts see cardiovascular disease in diabetes as primarily a lipid disease. You see how the lipid theory is working out in the statin debate. If we are honest, really honest with ourselves, we must admit to our knowledge gap in atherosclerosis. For instance, does anyone have even a clue as to when and how the vulnerable plaque ruptures? No TACT researcher is recommending patients go out and get chelated. Their goals are modest: they ask us to open our minds to the possibility of learning something.
Integrity of TACT trial methodology. That the TACT trial enrolled patients at sites where complementary and alternative medicine (CAM) is practiced roils the establishment. But what exactly bothers them about CAM practitioners? To posit that CAM-based caregivers are duping Americans implies you believe the average American is stupid—and in need of protection from purveyors of fish oil, niacin, and nonsteroidal anti-inflammatory drugs. Please. Dr Lamas told me that the favorable results of chelation do not surprise its practitioners. It's what they have observed for years. What's more, in the present subanalysis, researchers carefully looked at results based on sites and found no significance variance between CAM sites and "regular" medical practices.
And on the matter of misconduct of investigators at TACT trial sites, the idea of throwing stones in a glass house comes to mind. It's not as if mainstream medical science is pure. The Retraction Watch website hums with activity. Near-weekly reports of misconduct surface in clinical research. It seems the more sun we shine on science, the more we discover human nature. Whether in mainstream medicine or alternative medicine, humans will act like humans—and to think otherwise is deeply disingenuous and insulting. Such hubris is one of the many reasons the medical profession has fallen in stature.
Then there is the critique of the TACT trial design and statistics. The most frequently cited problem with TACT was its use of a composite end point. This is a legitimate point, and one acknowledged by the authors. The problem, of course, is that legions of cardiac drugs and devices have been approved based on clinical trials with such amalgamation. Influential cardiologist Dr Harlan Krumholz, writing in Forbes earlier this year, said, "The irony is that if a drug manufacturer had gotten this result, they would have celebrated. We have billion-dollar drugs like niacin and fenofibrate and ezetimibe that have less evidence than chelation therapy has now."
So the TACT trial is no different from standard cardiology trials—except in its positivity. At the AHA meeting this year, positive trials are rare. In fact, in recent years, heart meetings have become a parade of negative trials. In TACT, not only was the composite end point lower in the chelation group, so were deaths, coronary revascularization, and cardiovascular death.
One more note on the statistics of the current diabetic substudy. In an effort to be even more transparent and forthright, Dr Lamas reported what's called a Bonferroni correction for multiple subgroups. I'm no statistician, but I do read a lot of studies and rarely see this sort of extra vetting. Nonetheless, the primary end point remained highly significant.
It would be a huge mistake to dismiss this science because chelation does not conform to preconceived notions or because it is practiced outside the mainstream of medicine. Let's not forget about the patients with this terrible disease. It's not as if we have good treatments for them.
The authors have completely and thoroughly answered all questions posed to them. The trial has been repeatedly inspected and vetted in two prestigious peer-reviewed journals. Both the critics and TACT authors agree that it is too early to recommend chelation therapy. But surely the signal of benefit is strong enough to warrant confirmatory trials. It is time to replicate these findings.
Finally, as a trained observer, I have spent my whole life interacting with other humans. My assessment of Dr Lamas is that he is a good man whose scientific curiosity and open-mindedness brought him to a very inconvenient truth.
You can't change the rules in the middle of the game.
Cite this: Chelation Therapy: Promising for Diabetic Patients but Disruptive to the Medical Establishment - Medscape - Nov 20, 2013.