Fish Oils and CV Prevention — Now What?

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This transcript has been edited for clarity.

Tracy Y. Wang, MD, MHS, MSc: Hello. My name is Tracy Wang. I’m a professor of cardiology at Duke University, and I’m joined by Professor Renate Schnabel from the University Heart & Vascular Center Hamburg. Today we’re going to go over some of the very interesting fish oil trials that were just presented at the American Heart Association (AHA) Scientific Sessions.

Professor Schnabel, can you tell us a little bit about the VITAL Rhythm study?

Renate Schnabel, MD, MSc: Yes. It’s a pleasure for me to talk about the VITAL Rhythm study, which I commented on at the AHA. It’s popular in the community to take fish oil supplements for diverse reasons, but health benefits in terms of cardiovascular disease prevention have not been proven.

The VITAL Rhythm study program has several studies. The parent study was vitamin D and omega-3 fish oil at a dose of 1 g per day in order to reduce incidence of cardiovascular events compared with placebo for primary prevention in women 55 years or older and in men 50 years or older. This study was negative; there was no significant benefit for the intake of omega-3 fatty acids.

Therefore, the idea that atrial fibrillation possibly could be prevented through mechanisms of atherosclerosis, ischemic heart disease, or inflammation seen in atherosclerosis probably was not the right way to understand atrial fibrillation and possible benefits of fish oil intake. There have also been controversial studies that show the possible benefit — in particular, experimental data — because omega-3 fatty acids may have direct antiarrhythmic effects on myocytes, such as an effect on ion channels, electrical stabilizing effects, or stabilizing effects on the fluidity of cell membranes. Overall, this trial was negative too.

Wang: That’s very interesting because omega-3 fatty acids came on my radar several years ago with the original GISSI trials, showing that it had ventricular arrhythmic sudden cardiac death–protective effects. These atrial fibrillation results are very surprising for me.

I think the VITAL Rhythm trial is very interesting, especially in the context of some of the other trials that were presented at AHA. There was the STRENGTH trial, which was omega-3 carboxylic acid 4 g per day. It’s a combination of EPA and DHA, and the comparison was a corn oil placebo. The top-line results basically showed that after 4 years of follow-up, there was not a significant reduction in the risk for major adverse events. This was done in a population of patients where about half were secondary prevention and half were primary prevention.

We can also contrast that to the OMEMI trial. This was done completely in the secondary prevention population, and even more impressively, this was done in an older population of patients — aged 70 or 75 and above. This also looked at a combination of EPA and DHA and did not find a significant reduction in the incidence of major adverse cardiovascular events either.

Putting all of these trials together, let’s first talk a little bit about efficacy. Renate, it’d be great to hear your thoughts on this. Why is it that VITAL Rhythm, STRENGTH, and OMEMI did not really show what we expected in terms of efficacy?

Schnabel: We may not have targeted the right population or we may not have seen the right dose of fish oil preparation. I think that it’s not the right causal pathway. There may be no efficacy.

Although you are probably going to talk about the REDUCE-IT trial, these are really well-performed studies in primary and secondary prevention, covering a broad spectrum of patients, and there is absolutely no signal of benefit; you can talk about potential harm later on. I am no longer certain that there is a really significant beneficial effect and a real efficacy in this type of patient population.

EPA Dose vs Placebo

Wang: You brought up REDUCE-IT. This is what people have been talking about — how these trials have been different from REDUCE-IT. There are a couple of theories out there. One is that both of the STRENGTH and OMEMI trials looked at a combination pill of EPA and DHA, whereas REDUCE-IT was pure EPA. You can see that in terms of the level of EPA increase established in the STRENGTH trial, where it increased by about 200%; but in REDUCE-IT, it increased by about 400%.

There have also been theories floated by that the placebo may have contributed. The mineral oil used in REDUCE-IT does have some demonstrated increases in hsCRP and LDL associated with its use, whereas the corn oil placebos that were used in both the STRENGTH and OMEMI trials seem to have none of that biomarker evidence of inflammation or increased lipids. There have been discussions about the placebo selection as well.

There are obviously some other things, like the population studied. I mentioned that in the STRENGTH trial, it was about 50% secondary prevention; in the OMEMI trials, it was 100% secondary prevention. We also know that other trials, like the JELIS trial, for example, had a much lower rate, at about 20% secondary prevention. I’m not sure how much that population really plays a role because EPA had a significant effect in the JELIS trial.

One other thought I had was that maybe it also has to do with the statin dose that was used in the trial. In both STRENGTH and OMEMI, the high-intensity statin use rates were pretty high, around 50%; whereas the REDUCE-IT trial had a slightly lower rate of high-intensity statin use. I think all of these could really explain some of those differences.

I think what we need, at least from an efficacy standpoint, is another trial that looks at EPA vs corn oil so that we can settle this question once and for all. I really hope that study could be conducted.

Let’s look at this from a safety standpoint. We’ve got REDUCE-IT, STRENGTH, and OMEMI to a certain extent showing a signal that there might be a higher risk for atrial fibrillation if you use a 4 g/day dose of fish oil, whereas the VITAL Rhythm study showed no significant difference in atrial fibrillation. Renate, what do you think about that?

Increased Risk for AF?

Schnabel: I would not be too sure that there is really no difference. If you look at the VITAL Rhythm population, this was a primary prevention population, relatively young: 50 years and higher for men, 55 for women. And atrial fibrillation is a disease of older individuals. What we see is that, indeed, after 2.5-3 years, the survival curves appear to separate with a higher incidence of atrial fibrillation in the treatment group, which means under fish oil. Therefore, I would not say that the signal from the VITAL Rhythm study goes in a different direction and shows that there is no potential harm. Overall, as I said, the data on arrhythmias in total and atrial fibrillation are controversial for fish oil.

We don’t have long-term data on fish oil supplementation in experimental designs, but we know that there are acute effects. Different kinds of fish oil preparations given acutely with higher doses intravenously have an effect on sodium ion channels and calcium channels. We know also that there are longer-term effects. When they build into the cell membrane, they no longer have an effect on sodium channels but still inhibit calcium channels. That may be proarrhythmic.

Smaller studies in animal models have shown that there is a higher tendency of ischemia-driven arrhythmias after fish oil supplementation. Therefore, there is a possible explanation to why we see a higher risk for atrial fibrillation. If you look at the studies very closely, you see that the signal is pretty consistent. It’s not a high increase or a high risk, but there appears to be a possible increase in the risk of developing atrial fibrillation.

Wang: That makes a lot of sense to me. Let’s pull this all together. You’re an interventional cardiologist, so I’m sure you’re seeing these patients who have ASCVD or are at risk of having ASCVD. How do these trials now, when put into context, change your practice? Are you going to be using fish oil? If so, what kind and which patients?

Schnabel: At present, I would be very careful about using fish oil and prescribing fish oil either in primary or in secondary prevention. We’ll dissect the trials for their contents. There’s much more information in these trials. We’ll have lots of discussions over the next month and we may be able to find subgroups that might benefit. For now, however, I would not recommend prescribing fish oil for prevention of cardiovascular disease, and I’d maybe even start to rethink over-the-counter availability of fish oil supplements.

Wang: My take is a little different from yours. I’m certainly going to be much more cautious about who I use fish oil with. I still think that the REDUCE-IT trial showed a pretty impressive 25% risk reduction. The JELIS trial, which was the Japanese EPA trial, also had about a 20% risk reduction with a pure EPA form of fish oil.

I don’t think I’m going to go crazy and use it in all of my patients — and I haven’t — but I think there might still be some very high-risk patients for whom a pure, EPA-only drug might be helpful, especially those with high triglycerides.

The atrial fibrillation data really give me pause. In my patients who have paroxysmal atrial fibrillation, and maybe even other markers that suggest high risk for atrial fibrillation, I personally would hold off on applying these data to that group of patients, just out of safety concerns. That would be my take here, but I’m really hoping that we will be able to get another trial to settle this apples-to-oranges comparison, and hopefully do one that’s EPA-only vs perhaps a more neutral placebo so that we can settle the controversy.

Thank you very much for joining me for this interview, Renate. I hope you had a good AHA. I hope all of you out there listening in enjoyed the conversation. Thank you.

Schnabel: Thank you. It was a pleasure.

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