Case Closed: Multivitamins Should Not Be Used 1

The editorialists are fed up: “Enough is enough.” Writing about three new papers in the Annals of Internal Medicine that find no benefits for the use of multivitamins — only the latest in a long line of negative findings — Eliseo Guallar and colleagues write:

…we believe that the case is closed— supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful. These vitamins should not be used for chronic disease prevention. Enough is enough.

In the first paper,  Stephen Fortmann and colleagues performed an updated systematic evidence review of vitamin and mineral supplements for the US Preventive Services Task Force (USPSTF).

In the second paper, investigators from the Physicians Health Study II randomized nearly 6,000 physicians 65 years of age or older to  a multivitamin or a placebo.

In the third paper, Gervasio Lamas and his fellow investigators in the NIH’s Trial to Assess Chelation Therapy (TACT) randomized 1,708 patients who had had a heart attack to a multivitamin supplement or placebo.

Click here to read the full story on Forbes.

 

Screen Shot 2013-12-16 at 4.10.51 PM

Advertisements

TACT Principal Investigator Reflects On A Long And Contentious Journey Reply

In a fascinating and important blog post, Gervasio Lamas offers a deeply personal perspective on the long and contentious journey of the Trial to Assess Chelation Therapy (TACT), for which he was the principal investigator.

gervasio-lamasHere are a few quotes from his post, but I can’t urge you strongly enough to read the entire post over on CardioExchange. (Click here for my brief summary of 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.

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.

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.”

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.

 

TACT Substudy Suggests Possible Strong Benefit for Chelation in Diabetics Reply

One year ago the results of the TACT trial were published in JAMA, sparking an enormous controversy over the propriety of publishing a trial suggesting that chelation therapy might be beneficial in people with cardiovascular disease. Chelation therapy has long been a staple of alternative medicine, but until the publication of TACT it had received no credit whatsoever in mainstream medicine. TACT was supported by the NIH as part of an initiaitve to test the scientific basis of alternative medical therapies.

The JAMA paper reported positive results for the prespecified subgroup of patients who had diabetes at the start of the trial. Now a new paper, presented at the American Heart Association Scientific Sessions and published online in Circulation: Cardiovascular Quality and Outcomes, focuses on this important subgroup, and provides even stronger evidence for a possible benefit for chelation in patients with diabetes. The authors speculate that ethylene diamine tetra-acetic acid (EDTA) chelation might have an effect on metal-catalyzed oxidation reactions in the development of advanced glycation end-products, which appear to play a central role in diabetic complications.

The primary endpoint of the main trial – the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina – was significantly lowered from 30% in the placebo group to 26% in the chelation group (HR 0.82, 0.69-0.99, p=0.035).

Click here to read the full post on Forbes.

 

A Guide To The Raging Debate Over The NIH’s TACT Chelation Trial 7

(Updated) The publication in JAMA of the NIH’s Trial To Assess Chelation Therapy (TACT) trial has provoked a fascinating debate in the blogosphere. The vast majority of responsible physicians and healthcare professionals have little interest in chelation therapy per se, but the TACT trial has raised many important questions about the nature of medical evidence. Here’s a brief guide with links to some of the more interesting discussions (let me know if you are aware of other worthwhile discussions):

In the first of two accompanying editorials, the JAMA editors discuss some of the complex issues relating to TACT and explain why they decided to publish the TACT paper.

In a second accompanying editorial, Steve Nissen, while agreeing in principle with the idea that randomized controlled trials should be published, argues that the TACT investigators “fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate.”

TACT investigator Daniel Mark provided CardioBrief with a  detailed response to Nissen’s criticism. (Nissen declined to respond to Mark.)

Harlan Krumholz, in a blog post on Forbes, asked “what to do with inconvenient evidence”? He agrees with just about everyone else that TACT does not provide a reason to administer chelation therapy, but he argues forcefully that the results of the trial should not be simply dismissed.

Responding to Krumholz, Peter Lipson, also on Forbes, takes a position similar to Nissen’s that the trial was poorly performed and the results are highly questionable. The important things here are the responses to Lipson from Krumholz himself, Forbes pharma reporter Matt Herper, and Sanjay Kaul.

The most sustained assault on TACT, and on Krumholz’s position, comes from the highly-regarded skeptic blog Respectful Insolence written by Orac (the pseudonym of David Gorski, a surgical oncologist). In his take-no-prisoners assault on TACT, JAMA, and Krumholz, Orac writes “that JAMA is every bit as guilty as The Lancet was in 1998 when it published Andrew Wakefield’s antivaccine nonsense…. If published at all, TACT should have been published in some crappy, bottom-feeding journal, because that’s all that it deserves.” The comments section includes worthwhile exchanges between Orac and Sanjay Kaul and Matt Herper.

Finally (for now), Sanjay Kaul today summarized his defense of TACT (though he does not, of course, endorse chelation) in a blog post on CardioExchange. “Bottom line,” he writes, “in my opinion, the arguments that the TACT results are dubious or not valid are overstated. While the debate surrounding TACT is clearly warranted and welcome, I hope it generates more light than heat.”

Update:

Responding to the attacks on TACT from Orac and other members of the skeptical community, TACT investigator Dan Mark sent me the following comment on email, which he has agreed to share with my readers. The comment moves the debate in an entirely new and philosophical direction:

Although skepticism has an important role to play in critical debates, it is easy to overplay that hand. The people you mention seem to have a very naïve view of science, very far removed from the messy realities of daily work of people doing science. It is also important to remember that even the most hard core scientists can have some pretty eccentric views when they venture outside their narrow field of expertise. What does that imply about science and the people who wish to guard its borders?

There has been a project in philosophy to identify firm demarcation criteria that will allow for a distinction between science and pseudoscience. While some useful work has resulted, the overall attempt failed. Gets into some deep waters, but the harder the philosophers tried to find that electrified fence that marked off “real science” from the rest of human thought, the more they undermined the borders of science itself. Interestingly, “real scientists” rarely worry about whether they are doing science. They consider the question uninteresting, leaving it for the philosophers, sociologists and (now) the bloggers!

Controversial NIH Chelation Trial Published In JAMA Reply

Final results of the troubled NIH-sponsored TACT trial testing chelation therapy for coronary disease have now been published in JAMA. Last November, when the preliminary results were presented at the American Heart Association meeting, the positive finding in favor of chelation therapy surprised many observers, though the investigators and senior AHA representatives expressed considerable caution  about the proper interpretation of the results. Full publication of the main results should now allow for a more thorough consideration of the trial.

The Trial to Assess Chelation Therapy (TACT) was initially funded by the NIH more than a decade ago to test chelation therapy with EDTA, an alternative medicine therapy received by more than 100,000 people every year but with no evidence base for support. The highly controversial trial was temporarily suspended in 2008 in response to ethical concerns but was then allowed to resume. The trial was also hampered by slow enrollment, eventually resulting in a downsizing of the trial population. To maintain the trial’s power to achieve a meaningful result the follow-up time was increased. (Because of this change, and because the data and safety monitoring board reviewed the data multiple times over the course of the study, the threshold for statistical significance was lowered to 0.036.)

TACT was a double-blind study testing active or placebo infusions of chelation in 1,708 stable patients with a history of MI.  The primary endpoint of the trial– the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina– was significantly lowered in the chelation group:

  • 26% in the chelation group versus 30% in the placebo group (HR 0.82, 0.69-0.99, p=0.035)

Nissen

Steve Nissen

The editorial by the JAMA editors is itself evidence of the extraordinary sensitivity of the TACT trial. The JAMA editors, in a highly unusual situation, discuss their detailed review of TACT and explain their decision to publish the trial. Although they acknowledge multiple limitations of the trial, they defend its value: “reports of rigorous investigations should not be censored because of preexisting ideological positions,” they write.

In his editorial, Steve Nissen agrees with the JAMA editors decision to publish the trial but issues a fierce indictment of the trial and its conduct. The TACT paper, Nissen writes, “represents a situation in which many important limitations in the design and execution of a clinical trial compromise the reliability of the study and render the results difficult to interpret. Unfortunately, the efforts of these investigators fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate.”

Daniel Mark

Daniel Mark

TACT investigator Daniel Mark provided CardioBrief with the following detailed response to Nissen’s criticism. (Nissen declined to respond to Mark.)

In his editorial, Dr. Nissen asserts that the “logical” explanation for the greater withdrawals in the placebo group is that patients were unblinded. He further implies that the CAM sites were more likely to be responsible for such unmasking.

His editorial is written from the perspective of someone who is absolutely sure that the trial results are wrong and his mission is to identify where the flaws originate.

Click here to read the full story on Forbes.