Fish Oils and CV Prevention — Now What?

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This transcript has been edited for the sake of clarity.

Tracy Y. Wang, MD, MHS, MSc: Hello. My name is Tracy Wang. I am Professor of Cardiology at Duke University and Professor Renate Schnabel from the University’s Heart and 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 something about the VITAL Rhythm Study?

Renate Schnabel, MD, MSc: Yes. It’s a pleasure for me to speak about the VITAL Rhythm study that I commented on at the AHA. Taking fish oil supplements is popular in the community for a variety of reasons, but health benefits in terms of preventing cardiovascular disease have not been demonstrated.

The VITAL Rhythm study program comprises several studies. The parent study consisted of vitamin D and omega-3 fish oil at a dose of 1 g per day to reduce the frequency of cardiovascular events compared to placebo for primary prevention in women aged 55 and over and in men aged 50 and over. This study was negative; There was no significant benefit to omega-3 fatty acid intake.

Hence, the idea that atrial fibrillation could possibly be prevented by mechanisms of atherosclerosis, ischemic heart disease, or inflammation in atherosclerosis was probably not the right way to understand atrial fibrillation and possible benefits of fish oil intake. There have also been controversial studies showing the potential benefits, particularly experimental data, as omega-3 fatty acids can have direct antiarrhythmic effects on myocytes, such as: B. an effect on ion channels, electrical stabilization effects or stabilizing effects on the flowability of cell membranes. Overall, this study was also negative.

Wang: This is very interesting because omega-3 fatty acids came on my radar a few years ago with the original GISSI studies and showed that they had ventricular arrhythmic sudden cardiac death protection effects. These atrial fibrillation results are very surprising to me.

I think the VITAL Rhythm study is very interesting, especially in the context of some of the other studies that were presented at the AHA. There was the STRENGTH study, which was 4 grams of omega-3 carboxylic acid per day. It’s a combination of EPA and DHA, and the comparison was a corn oil placebo. The top-line results essentially showed that after 4 years of follow-up the risk of serious adverse events was not significantly reduced. This was done in a population of patients in whom approximately half were secondary prevention and half were primary prevention.

We can also contrast that with the OMEMI study. This was done entirely in the secondary prevention population, and more impressively it was done in an elderly patient population aged 70 or 75 years and over. This also affected a combination of EPA and DHA and also did not result in a significant reduction in the incidence of serious adverse cardiovascular events.

First, let’s summarize all of these studies and talk a little about their effectiveness. Renate, it would be great to hear your thoughts on this. Why didn’t VITAL Rhythm, STRENGTH and OMEMI really show what we expected in terms of effectiveness?

Schnabel: We may not have selected the right population or we may not have seen the right dose of fish oil supplement. I think it’s not the right causal path. There may be no effectiveness.

While you will likely be talking about the REDUCE-IT study, they are really well-run primary and secondary prevention studies that cover a wide range of patients and there is absolutely no signal of any benefit. You can talk about possible damage later. I am no longer sure that there is any really significant positive effect and effectiveness in this type of patient population.

EPA dose versus placebo

Wang: You mentioned REDUCE-IT. This is what people were talking about – how these attempts were different from REDUCE-IT. There are a couple of theories out there. One of them is that both the STRENGTH and OMEMI studies examined a combination pill made from EPA and DHA, while REDUCE-IT was pure EPA. You can tell by the EPA increase found in the STRENGTH study, where it increased by about 200%. In REDUCE-IT, however, it increased by around 400%.

Theories have also been suggested that the placebo may have contributed to this. The mineral oil used in REDUCE-IT has some proven increases in hsCRP and LDL, while the corn oil placebo used in the STRENGTH and OMEMI studies have none of these biomarker indications of inflammation or elevated lipids. There were also discussions about placebo choices.

There are obviously some other things like the population studied. I mentioned that the STRENGTH study was about 50% secondary prevention; The OMEMI studies were 100% secondary prevention. We also know that other studies, such as the JELIS study, had a much lower rate with a secondary prevention of around 20%. I’m not sure to what extent this population really matters as the EPA had a significant effect in the JELIS study.

Another thought I had was that it might also have to do with the statin dose that was used in the study. For both STRENGTH and OMEMI, high-intensity statin use rates were quite high at around 50%. While the REDUCE-IT study showed a slightly lower rate of high-intensity statin use. I think all of this could really explain some of these differences.

I think what we need at least from an efficacy standpoint is another study looking at EPA versus corn oil so that we can sort this out once and for all. I really hope that the study could be carried out.

Let’s look at this from a security point of view. We did REDUCE-IT, STRENGTH and OMEMI to some degree, which shows a signal that there is a higher risk of atrial fibrillation when using a dose of 4g / day fish oil, while the VITAL Rhythm study showed no significant results in the difference Atrial fibrillation. Renate, what do you think of that?

Increased risk for AF?

Schnabel: I wouldn’t be sure if there really is no difference. If you look at the VITAL Rhythm population, it was a relatively young primary prevention population: 50 years and above for men, 55 years for women. And atrial fibrillation is a disease of the elderly. What we see is that after 2.5 to 3 years, the survival curves actually seem to separate with a higher incidence of atrial fibrillation in the treatment group, that is, on fish oil. So I wouldn’t say the signal from the VITAL Rhythm study is going any other way and showing that there is no potential harm. Overall, as I said, the data on arrhythmias in total and atrial fibrillation for fish oil are controversial.

We don’t have long-term data on fish oil supplementation in designs, but we do know that there are acute effects. Different types of fish oil supplements that are acutely administered intravenously at higher doses affect sodium ion and calcium channels. We also know that there are longer term effects. When they are built into the cell membrane, they no longer act on sodium channels, but continue to inhibit calcium channels. This can be proarrhythmic.

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

Wang: That makes a lot of sense to me. Let’s sum it all up. You’re an interventional cardiologist so I’m sure you see these patients who have ASCVD or are at risk for ASCVD. Now, when put into context, how do these experiments change your practice? Are you going to use fish oil? If so, which type and which patient?

Schnabel: At the moment I would be very careful when using fish oil and prescribing fish oil for either primary or secondary prevention. We will examine the experiments for their content. There is much more information in these studies. We will have a lot of discussion over the next month and possibly find sub-groups that could benefit from this. Right now, however, I wouldn’t recommend prescribing fish oil for cardiovascular disease prevention, and I might even start rethinking the over-the-counter availability of fish oil supplements.

Wang: My attitude is a little different from yours. I will certainly be a lot more careful who I use fish oil with. I still think the REDUCE-IT study showed an impressive 25% risk reduction. The JELIS study, which was the Japanese EPA study, also had a risk reduction of about 20% with a pure EPA form of fish oil.

I don’t think I’m going to go crazy and use it on all of my patients – and I haven’t – but I think there are still some very high risk patients out there for whom drug-only is only suitable for EPA is helpful, especially those with high triglycerides.

The data on atrial fibrillation really makes me pause. In the case of my patients with paroxysmal atrial fibrillation and possibly even other markers that indicate a high risk of atrial fibrillation, I would be reluctant to apply this data to this group of patients for safety reasons. That would be my opinion here, but I really hope we will be able to do one more attempt to settle this apple-to-orange comparison, and hopefully one that is just EPA versus perhaps a more neutral placebo so that we can settle the controversy.

Thank you for joining me for this interview, Renate. I hope you had a good AHA. I hope all of you out there who listened enjoyed the conversation. Many Thanks.

Schnabel: Thank you. It was a pleasure.

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