The recent retraction—and immediate revised publication—of the landmark PREDIMED trial left many people wondering whether the New England Journal of Medicine (NEJM) had yanked out a tablecloth and left the table perfectly set, or whether it was suddenly raining plates, forks, and knives.
The revised study addressed some statistical problems identified a year ago by another researcher who was not involved with the study. However, the findings remained largely the same: that a Mediterranean diet improves cardiovascular outcomes. The original trial results were published in 2013, and the study has spawned many other related studies on the merits of a diet rich in olive oil and nuts.
"I think that what we saw in the retraction was a signal that the data had major flaws," said John P.A. Ioannidis, MD, DSc, Stanford University, California. "Clearly, the retraction was the right thing to do. However, even after the retraction, I don't think that we have seen the whole story."
Ioannidis, a well-known critic of medical research that is not science-based, was recording a video interview with Medscape Editor-in-Chief Eric Topol, MD, when the topic of PREDIMED came up. This article is based on an excerpt of their talk.
"I think that the problem that was detected by the statistical analysis," Ioannidis said, "is not explained by the correction that led to the republication. So my strong belief is that PREDIMED is a seriously flawed trial.
"I cannot trust it any longer."
Ioannidis explained that he was very happy when PREDIMED was first published, as he generally views the field of nutrition epidemiology as "a mess."
"I have long advocated that we can fix some of that mess by running large-scale, long-term randomized trials with clinical endpoints," he told Topol. "PREDIMED was a trial that tried to do that. It was pretty much the exception compared to that huge mess of nutritional epidemiology. So I was very happy to see it published. I was very excited that at last we were making some progress."
"But over the years I was also feeling uneasy about the fact that PREDIMED was being presented and republished and reanalyzed in the very same way as you see with observational epidemiology."
Other researchers published "zillions" of studies based on the trial's findings, with conclusions that were far more tenuous, Ioannidis said.
So when the whistle was blown on the methodology and the data for the original trial, he had serious misgivings about its findings.
"I love olive oil," he confessed.
"Yeah, you're Greek!" Topol said with a chuckle.
"I'm sorry," Ioannidis responded. "I cannot trust it. There are major problems that go beyond the retraction... And I think that republishing a trial with seemingly the same results is not going to fix it.
"In the case of PREDIMED, I would argue that one would have to obtain all of the raw data—not the clean data, the raw data—before arbitration, for an independent committee to analyze. And I think if that were to happen, my bet is that the effect sizes would shrink or even go away.
"I would hate to see that. I would like to bet against my own prediction. But I think there are some very serious problems when we trust trials that have no transparency. They are not willing to go through re-analysis; they are not willing to have some independent scrutiny on what is going on. This is still [true for] the majority of randomized trials being published."
Topol expressed surprise that the editors of NEJM had not pushed harder for more transparency, particularly with such an unprecedented case, and Ioannidis agreed.
"I still hope that they will allow some further probing into this trial," Ioannidis said. "I think it would be a lost opportunity if we don't learn more, because I think it's just the tip of the iceberg. There's far more that's going on, and I think that PREDIMED may be the most honest, in a way, compared to other trials that may be less honest."
Topol was clearly struck by that conclusion. "Well," he said, "that's saying a lot there."
Watch the Medscape site for the full interview between Topol and Ioannidis, to post in the near future.
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Cite this: Mediterranean Diet Study 'Seriously Flawed': Ioannidis - Medscape - Jun 19, 2018.