The TACT diabetes substudy: How far can the apple fall from the tree?

The other day in the doctors lounge a colleague asked me if I had heard about a new study presented at AHA showing a benefit of chelation therapy in diabetics. I'm not big on sound bite medicine and often don't get around to reading, let alone blogging about such things for a month or more. So I told him no I hadn't, but it had better be an improvement over the recent TACT study, which I thought was seriously flawed.

I found it Saturday over morning coffee. And no, it was not an improvement over TACT. It was merely a subgroup analysis of TACT itself. Most of you have heard the buzz by now so I'll cut straight to the study, which was simultaneously published in one of the Circulation journals. Here's the link. From the paper:

Methods and Results—Patients received 40 infusions of EDTA chelation or placebo. A total of 633 (37%) patients had diabetes mellitus (322 EDTA and 311 placebo). EDTA reduced the primary end point (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina; 25% versus 38%; hazard ratio, 0.59; 95% confidence interval [CI], 0.44–0.79; P less than 0.001) for over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI, 0.39–0.88; adjusted P=0.002). All-cause mortality was reduced by EDTA chelation (10% versus 16%; hazard ratio, 0.57; 95% CI, 0.36–0.88; P=0.011), as was the secondary end point (cardiovascular death, reinfarction, or stroke; 11% versus 17%; hazard ratio, 0.60; 95% CI, 0.39–0.91; P=0.017). However, after adjusting for multiple subgroups, those results were no longer significant. The number needed to treat to reduce 1 primary end point over 5 years was 6.5 (95% CI, 4.4–12.7). There was no reduction in events in non–diabetes mellitus (n=1075; P=0.877), resulting in a treatment by diabetes mellitus interaction (P=0.004).

Conclusions—Post–myocardial infarction patients with diabetes mellitus aged greater than or equal to 50 demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. However, they do not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes mellitus.

The hype surrounding this paper will be misleading. Before I get to that, some other links of interest. Here is a discussion piece from the Heart.org, now part of Medscape Cardiology (free full text after registration). The piece is less than appropriately critical of the study but does provide some details for those without full text access to the original paper. Also found at the Medscape site is this article by Dr. John Mandrola (who blogs at Dr. John M). I think Dr. John is way too kind to the study and his tone, as reflected in the title Chelation Therapy: Promising for Diabetic Patients but Disruptive to the Medical Establishment is a little incendiary. From his introductory comments:

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.

What does he mean by the medical establishment? If he means an organized body of leaders in medicine who stand for good ethics and scientific integrity, put me in that camp. That medical establishment has good reason to be upset about TACT. But perhaps Dr. John means something different. He says:

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.

Dr. John is talking around a very serious accusation: that professionals in mainstream medicine don't want patients to get well and stay well by taking charge of their own health. It's a somewhat conspiratorial idea but popular enough. The suggestion is that doctors in conventional medicine don't want their patients to be empowered. Is that what he really meant?

How should we interpret the study? First the usual objections. Be cautious about basing treatment recommendations on just one trial. PROWESS and many other studies taught us that lesson. (And keep in mind that TACT is just one in the face of several prior studies all of which were negative). Moreover we all know the hazards of subgroup analysis.

But more telling is a look at the peculiarities of TACT itself. With the publication of the original study in JAMA there was a companion editorial by Dr. Steve Nissen that was appropriately critical. He said:

Execution of a high-quality RCT requires skilled investigators and study coordinators who understand these critical scientific principles. For TACT, more than 60% of patients were randomized at enrolling centers described as complementary and alternative medicine sites. Many of these centers have websites that describe their services, which include an array of unproven therapies ranging from stem cell therapy to regrow breasts after mastectomy, high-dose intravenous vitamin C to treat cancer, and use of cinnamon for treating diabetes to treatment of influenza with antimicrobial essential oils or homeopathic remedies (while warning patients not to undergo immunization). Other sites offer chelation to treat or cure a variety of conditions including autism in children. 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. Whether a high-quality RCT can be performed at such sites is questionable.

For an in depth look at what Nissen was referring to this article by Atwood and colleagues is a must read. It reviews prior negative studies and exposes what was really going on with TACT and, I believe, is prerequisite to understanding the findings. It's compelling reading and what you get from it is that TACT was badly (and in my reading of the paper, hopelessly) flawed. That's why I ask in title of this post how far the apple of the diabetes substudy can fall from the tree of TACT.

What's the take-home message? Here's Dr. John's:

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.

I agree with him that this represents insufficient evidence to change practice. I also agree we shouldn't dismiss something just because it's outside mainstream. But the concerns about TACT are more basic. They are about ethics and scientific standards. My take on the study is not as optimistic as Dr. John's.

Not only was TACT just one positive trial in the face of several negative studies (a Bayesian analysis, I suspect, would be unfavorable) but it was an anomaly. It's hard to read the Atwood paper and not come away thinking this trial was uniquely flawed. Whether the findings of the TACT substudy even warrant further research could be vigorously debated.