In the News: Important Updates on the PREDIMED Study

You know, there are certain things that just deserve to be responded to very, very quickly because they, in the absence of proper response, can have a spreading effect and send misinformation out into the universe. It gets replicated. Such is the case in this extraordinary example, just in the month of June in 2018 of the predimed study, this extraordinary landmark study done in Spain and other Mediterranean countries that looked at the effect of a Mediterranean diet on cardiovascular disease risk. And you might recall in 2013, in the new England Journal of Medicine, a summary of this paper was published, an editorial actually, which was a really interesting editorial entitled Something New under the the Mediterranean Diet and Cardiovascular Health, which was really speaking to the results of this paper that appeared in the journal entitled Primary Prevention of Cardiovascular Disease with the Mediterranean D, the principal investigator being Miguel Angel Martinez Gonzalez. And of all the papers that we've seen and all the studies that have been published in nutrition intervention, this one has to stand out as one of the most important studies that showed a very significant reduction in risk by those individuals who administered or complied with a Mediterranean diet, olive oil and nuts included. And it was seemingly a very well structured and well done study, occupied thousands of individuals over a lengthy period of time. We've reviewed this in the past and it has set a tone for clinical trials in the area of nutrition intervention and the importance of nutrition as a primary therapeutic tool for the reduction of one of the most significant diseases in our culture, which is cardiovascular disease. And everything looked fine until Dr. Carlisle, anesthesiologist, started looking at clinical trials in the field of anesthesiology, particularly by a Japanese investigator that had over 160 papers that he had published on various intervention trials in anesthesiology. And Carlyle took exception to kind of these tones of these papers and decided he'd look at the procedures a little more closely. In so doing, he eventually taught himself statistics, got outside support for looking at this, and found that not only were these studies not properly randomized that Fuji had published, but they probably deserved to be retracted because the conclusions may be flawed. And in fact they resulted in the retraction in all these journals of these studies of more than 160 papers, making these studies of this anesthesiologist in Japan the most retracted scientist in the history of published research. But Carlisle didn't stop there. He went on and examined many other clinical trials in other fields to see if this new way of looking at randomization that he had developed would pick out flaws in other studies. And out of the 5,000 papers that he Examined in the New England Journal of medicine, he found 11 that seemed to be similarly flawed as it relates to the randomization procedure in these clinical trials, one of which was the prediment study that resulted then in further looking that Professor Gonzales actually enlisted a team of experts to come in and look at the data. And they found that lo and behold, Carlyle was right. There were some problems in randomization, for instance, in a village that was involved in this in Italy, where they should have been randomized, it turned out that the whole village wanted to have the free olive oil. And so they all were on the program rather than randomization as should have taken place. So that resulted then in the New English Journal of Medicine retracting this landmark paper in 2013 on the Mediterranean diet and cardiovascular disease. This is a seismic kind of implication as it relates to the fundamental evidence that supports nutrition intervention. Well, from that then the clock runs very rapidly forward. We see reports on all the major media, including National Public Radio and public television, discussing the implications of these studies and the impact and then coming to recognize that we don't just sit at rest, that we could recast this data. And so the group in Spain with Martinez Gonzales et al, once again took out the confounders of the non randomized individuals, relooked at the statistics and lo and behold found fortunately that the data conclusions hadn't been supported even by removal of the non randomized individuals, and that there was a significant reduction in risk in cardiovascular disease and those that were adherent to the Mediterranean diet. That led then to the first time that I have ever seen this happen. A republishing of this paper now in the June 21 issue of 2018 in the New England Journal of Medicine entitled Primary Prevention of Cardiovascular Disease of the Mediterranean Diet supplemented with extra virgin olive oil or nuts. So it's basically the same data set as the 2013 study with the removal of the non randomized individuals and a redoing of the statistics. Now, I think it's important for the sake of understanding as to how this was managed in the scientific literature. And it turns out that there is just a subtle but kind of important difference in the conclusions of these two studies. Whereas in the 2013 study, and I'm going to quote directly, the conclusion was among persons at high cardiovascular risk, Mediterranean diet supplemented with extra virgin olive oil or nuts reduced the incidence of major cardiovascular events. That's the conclusion of the 2013 trial. Now, the 2018 recalculated and redone statistics without the groups that were not randomized. Here are the conclusions of this trial, same data, same subjects, but just with a different data analysis. In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra virgin olive oil or nuts than among those assigned to a reduced fat diet. Now, you'll notice it's a very subtle but kind of important difference between the two. Whereas in the original 2013 study it said a Mediterranean diet supplement, extra virgin olive oil and nuts reduced the incidence, meaning there seemed to be a causative effect. In the 2018 repurposing of the data, they said that it was a lowered incidence. They're not saying that it had a prime. They can't say it had a primary effect as the cause. So there's a slight difference in the phraseology, with the conclusion still about a 30% reduction in incidence of those that were on the Mediterranean diet in both of those studies. So the point I want to leave you with is these are one of the problems that we encounter with dietary intervention trials over longer duration compliance. And it's not the same as lab rats in a controlled study. It's not even the same as a human trial in short term, which is often done in pharmaceutical medicine for a drug. But these longer term dietary interventions with ad lib patients that are out in the world at large are very complicated to get clean data. And I want to compliment the Martinez Gonzalez group for their heads up and their direct way they've approached us also for the study design and the recognition of some of the flaws in the randomization. But I think the important takeaway that all of us should remember is that the conclusion of the trial is still very positive for a Mediterranean diet intervention with individuals of cardiovascular disease risk in lowering their risk significantly by approximately 30%, which is, by the way, comparable with any other kind of clinical trial that's been done on a pharmaceutical preparation over the period of time of this study. So I think that the outcome is no different than was discussed really in this editorial. Something new under the sun, the Mediterranean diet and cardiovascular health. But the specifics of the trial leads us to really be very, very cautious about looking at the details of clinical trial design and their execution so that we understand where reality and evidence resides. But this trial should be seen as a very positive continuing step forward in our understanding of the powerful role of that personalized lifestyle intervention has in chronic disease incidence risk reduction.