Todd Whitthorne talked with Dr. Nina Radford, about the systematic review and meta-analysis Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events published in the JAMA September 12, 2012, Vol 308, No 10 issue. Click here if you would prefer to listen to the interview.
Todd: Hello once again this is Todd Whitthorne with another healthy living podcast and I’m joined today by Dr. Nina Radford, the Head of Cardiology for the Cooper Clinic and we’re going to talk about a recent article in JAMA that discussed a meta-analysis of omega-3 as it relates to the cardiovascular benefits. So Dr. Radford, this can be a rather complicated topic because we’re talking about statistics and scientific research, but I do know we have a very educated and inquisitive listening audience, so let’s walk through this paper because the headlines we’ve seen in the newspapers or heard on the radio basically came out and said that “omega-3, or fish oil, did not show benefit for cardiovascular health.” Can we dig a little deeper and explain really what this paper was investigating, and what the results showed?
Dr. Radford: Absolutely! I’m just delighted to discuss this with you because as we both know, sometimes these very important papers get condensed into a single, simple sentence or headline that may peak an individual’s attention but doesn’t always tell the whole story…, and this paper I think is a good example of that.
So this paper is a meta-analysis, and what that means is it is combining information from multiple studies, and why would you want to do that? Well, if you combine studies together your population will grow, so for example in this meta-analysis they combined the data from 20 studies so it included almost 69,000 patients. When you have a larger patient population, it’s easier to see small effects that may occur that may be statistically significant. The problem with combining studies is that all studies are a little bit different… the ages of the patient may be different; the formulation of the omega-3 being used may be different; they time they use the omega-3 may be very different; it may be in a different country where native foods are very different for example, from the United States. So, one of the problems is that when you combine studies that are very different, and you reach conclusions from them, your house is sort of built of rickety wood, so you have to be careful in terms of how you interpret it. That being said, what we have are this combination of 20 studies. The median age is 68, and I’ll remind you median means that 50% or below that age, and 50% are above, and in these studies the age range was 49 to 70. In these studies, the median dose of omega-3 was about a gram, and that’s probably less than most people consider taking daily today.
Todd: I’m sorry. That’s a gram of EPA plus DHA, not a gram of fish oil, correct?
Dr. Radford: That’s correct. And the range was from .53, so half a gram, which most of us would consider on the lower side, to 1.8 grams per day. The treatment duration was about two years and spanned from one to six, and the important thing about these studies is that 13 of the 20 were secondary prevention studies. What that means is those participants had already been diagnosed with heart disease. They had heart attack, bypass, heart failure, sudden death, stents, but they were not people who were taking it to prevent the first event. Rather, these were people who were put on fish oil to prevent a second cardiovascular event or death. Four of the studies were mixed primary secondary, you couldn’t really sort out which was which, and three of the studies had to do with preventing sudden death in people who had implantable cardiac defibrillators (those are the internal defibrillators that shock you if you have a potentially life-threatening heart rhythm abnormality). So again, these are patients who are older, they have known heart disease, and they’re taking EPA plus DHA at a median of a gram for about two years.
Now, one of the things that we have to remember in all of this is that there’s pretty good reason to think that fish oil may help when we look at basic science. There have been studies that suggest it lowers blood pressure, lowers triglycerides, may stabilize heart rhythms, may reduce the stickiness of the blood to form to form blood clots, so there’s some good rationale from which these studies were conducted, and that’s always sort of reassuring to know there’s some basic science that underlies these. So in this analysis, they looked at five major outcomes – all cause mortality (that’s the risk of dying of anything); cardiac death (dying of heart attack); they looked at sudden death (which is a heart rhythm abnormality); rather than having a heart attack and then having heart failure, for example; having a nonfatal heart attack; or stroke.
When we look at whether or not a result is statistically significant, we look at something called the P value, and the P value helps us decide if this result that could happen by chance, or is this the result that can withstand rigorous statistical testing? And we rely on that P value as readers of medical science, to let us know yes, that’s statistically significant, or no it’s not. We don’t just rely on the number that we see, we have to rely on the statistics to back it up, so in this population is that meaningful.
Now, in most studies that I read, a P value of significance is a P value less than 0.05. When you know that the P value is less than that, you know it’s statistically significant. And when we look at that range of P value in this study, there was actually a demonstrated benefit in terms of reducing cardiac death. It reduced it by about 9 percent. Now, what’s made this somewhat controversial is these authors have decided to make a much more limited P value of .0063, and that’s rather usual, and that requires that the effect be more robust if you will, in order to prove that it’s present.
And when we look at studies – for example you may remember testing hormone replacement, and did hormone replacement reduce the risk of death for example? In all of those studies the P value is 0.05. If you look at whether statin medications reduce the risk of dying from heart disease, the P value is 05. So the use of this very, very small P value, is a little unusual and not everybody is accepting it when we look at this study. So certainly, what I would conclude from this study, based on a P value I think is reasonable, is that there is likely a small reduction in cardiac death in the studies of patients who are older and already had advanced heart disease.
One of the things I think is very interesting in this paper is that they provide sort of a chronologic history. They start with studies done in the mid- 1995’s and they go through the studies that were published more recently in 2012. And what’s interesting is in the studies that were published in the in the mid-to-late 90s until 2005, there was a benefit of omega-3 in terms of all cause mortality. But when you look at the most recent studies that were published in 2010 or 2012 you did not see that effect. So does that mean that the studies that were done early on were wrong? Absolutely not! What we see is an effect of improving medical science and improving technology. Compared to 1995, patients who are treated after a heart attack today are treated with much more sophisticated medications. Their lipids are much more aggressively lowered compared to patients in 1995, so if I add a therapy like omega-3 fatty acids, which have a small benefit compared to those other therapies, it may be hard to see that benefit unless you have an extraordinarily large number of patients in the trial. And so, I don’t see this as being a call to throw away all your fish oil. Rather, I see this as a recommendation that there is likely is benefit, but it’s small, compared to the other known therapies that we have for patients treated after a heart attack. Now let me be very clear that this has no bearing on patients who haven’t heart disease yet; who haven’t had their first heart attack yet. Maybe they have high cholesterol. Maybe they have a strong family history of developing heart disease and they want to prevent their first event. This paper doesn’t address population all.
Todd: Clearly, what’s interesting about omega-3, is that there are literally thousands of studies that have been done looking at the various and assorted benefits and in a variety of areas, but in particular cardiovascular disease. So for someone healthy, someone that is just looking to improve their overall cardiovascular risk profile, omega-3 still make sense from your perspective as a cardiologist?
Dr. Radford: I think that they definitely ought to be offered to patients. I think that they definitely may have some benefits in terms of reducing death from cardiovascular disease. I think compared to their other therapies, like statin medications or low dose daily aspirin, that effects may be small, but every little bit helps if we’re talking about reducing your risk of dying of heart disease.
Todd: And that main benefit as we hear so much about inflammation, that seems to be the benefit of omega-3, as an anti-inflammatory?
Dr. Radford: And there may be benefits well beyond that, that we simply don’t have enough knowledge about.
Todd: Very good. Well Dr. Radford, as always I appreciate your insight. It’s like going to Paul Harvey for the rest of the story, to break it down and simplify something that is very, very complex, so we appreciate it.
Folks, if you want more information, you can sign up for The Cooperized Newsletter. As always, we’ll keep you updated with whatever we can here on the podcast and on the website. Until next time, this is Todd Whitthorne. Have a great day. Be healthy.
This information is very important to get out to all those interested in fish oil benefits. I hope you will convert this to an article that is included in a Cooperized e-newsletter. I do have a couple of suggestions for improvement.
1. More information is needed for non-technical people to really understand p statistic. I would suggest explaining that the confidence interval is 1 minus the p statistic, which means the authors chose a confidence interval of 99.4% when research studies normally use a 95% confidence interval. If you raise the confidence interval high enough in a study, you can almost certainly never find any benefits. Dr. William Harris suggests that a 90% confidence interval is more suited to the test of something that has almost no side effects, which I completely agree.
2. According to Dr. William Harris, on page 3 they demonstated certain benefits. Dr. William Harris’s comments posted on the internet are as follows:
“They showed in Figure 3 that there was a significant benefit of omega-3 on cardiac death, and trends towards benefit in total mortality, sudden death and MI (plus trends towards increased stroke). ”
3. A discussion that most studies for very specific situations that have shown benefits have used dosages of 2 to 4 grams. This will significantly help understand the low level in the studies used. This is discussed extensively in Dr. Joseph Maroon’s book on Fish Oil.
Thank you for taking the time to share your thoughts with us.You defnintely have read up on the subject. Dr. Harris was interviewed earlier this fall in another podcast. We also appreciate the research Dr. Maroon has done.
Regarding p values, I actually Google’d p values in hopes I’d find a “p values for idiots guide” but didn’t come up with anything that wasn’t fairly confusing. I love the example you’ve given – we all understand the swing between 99.4% and 95%.
Of interest, JAMA has published 16 meta-analyses this year. The first 15 used a p value of .05. The 16th, this analysis, used .006.