This transcript has been edited for the sake of clarity.
Tracy Y. Wang, MD, MHS, MSc: Hello. My name is Tracy Wang. I am a professor of cardiology at Duke University and I am supported by Professor Renate Schnabel from the University Heart and Vascular Center Hamburg. Today we’re going to go over some of the very interesting fish oil studies 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. It is popular in the community to take fish oil supplements for a variety of reasons, but the health benefits in terms of preventing cardiovascular disease have not been established.
The VITAL Rhythm course comprises several courses. The parent study included vitamin D and omega-3 fish oil at a dose of 1 g per day to reduce the incidence 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.
Therefore, the idea that atrial fibrillation could possibly be prevented by mechanisms of atherosclerosis, ischemic heart disease, or inflammation in atherosclerosis was probably not the way to understand atrial fibrillation and potential benefits of taking fish oil. There have also been controversial studies that demonstrate the potential benefits – especially experimental data – because omega-3 fatty acids can 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 study was also negative.
Wang: That’s very interesting because omega-3s came on my radar a few years ago with the original GISSI studies and showed that they protect against ventricular arrhythmic sudden cardiac death – a protective effect. 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 contained 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 essentially showed that there was no significant reduction in the risk of serious adverse events after 4 years of follow-up. This was done in a patient population with about half for secondary prevention and the other for primary prevention.
We can also contrast that with the OMEMI study. This was done entirely in the secondary prevention population, and it was even more impressive in an elderly patient population – aged 70 or 75 and over. This also examined a combination of EPA and DHA and also found no significant reduction in the incidence of serious adverse cardiovascular events.
When we put all of these attempts together, let’s talk a little about the effectiveness first. Renate, it would be nice 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 addressed the right population or seen the right dose of the fish oil preparation. I think this is not the right causal route. There can be no effectiveness.
While you are likely to be talking about the REDUCE-IT study, these are really well-conducted studies in primary and secondary prevention covering a wide range of patients and there is absolutely no evidence of any benefit; You can talk about possible damage later. I am no longer sure that there is a really significant positive effect and effectiveness in this type of patient population.
EPA dose vs. placebo
Wang: You mentioned REDUCE-IT. This is what people have been talking about – how these studies differ from REDUCE-IT. There are a couple of theories. One is that both the STRENGTH and OMEMI studies looked at a combination pill of EPA and DHA, while REDUCE-IT was pure EPA. You can see this in terms of the EPA surge found in the STRENGTH study, where it increased by about 200%; at REDUCE-IT, however, increased by around 400%.
There have also been theories that the placebo may have contributed. The mineral oil used in REDUCE-IT has some proven increases in hsCRP and LDL related to its use, while the corn oil placebos used in both the STRENGTH and OMEMI studies have none of this biomarker evidence for Seem to have inflammation or elevated lipids. There were also discussions about placebo choices.
There are obviously a few other things, like the population studied. I mentioned that in the STRENGTH study it was about 50% secondary prevention; in the OMEMI studies it was 100% secondary prevention. We also know that other studies, such as the JELIS study, had a much lower rate with around 20% secondary prevention. I’m not sure to what extent this population really matters as EPA had a significant impact on the JELIS study.
Another thought I had was that it might also have to do with the dose of statin that was used in the study. For both STRENGTH and OMEMI, high-intensity statin use rates were quite high, around 50%; while the REDUCE-IT study showed a slightly lower rate of high-intensity statin users. 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 comparing EPA to corn oil so we can sort this out once and for all. I very much hope that the study can be carried out.
Let’s consider this for security reasons. We have REDUCE-IT, STRENGTH, and OMEMI which, to some extent, show a signal that there might be a higher risk of atrial fibrillation when using a dose of 4g of fish oil per day, while the VITAL Rhythm study did not make any significant ones Results showed difference in atrial fibrillation. Renate, what do you think of that?
Increased risk of atrial fibrillation?
Schnabel: I wouldn’t be sure if there really is no difference. Looking at the VITAL Rhythm population, it is a relatively young primary prevention population: 50 years and older for men, 55 years for women. And atrial fibrillation is a condition affecting the elderly. What we see is that the survival curves actually seem to separate after 2.5-3 years with a higher incidence of atrial fibrillation in the treatment group, that is, on fish oil. So I wouldn’t say that the signal from the VITAL Rhythm study is going in a different direction and showing that there is no potential harm. Overall, as noted, the data on total arrhythmias and atrial fibrillation for fish oil are controversial.
We don’t have long-term data on fish oil supplementation in experimental designs, but we do know that there are acute effects. Various types of fish oil supplements that are acutely administered intravenously at higher doses have an effect on sodium ion channels and calcium channels. We also know that there are longer-term effects. When incorporated 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 there is a higher tendency for ischemic arrhythmias after fish oil supplementation. Hence, there is a possible explanation for why we see a higher risk of atrial fibrillation. If you look 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 pull it all together. You’re an interventional cardiologist so I’m sure you see these patients who have or are at risk of ASCVD. Now, when put in context, how do these experiments change your practice? Are you going to use fish oil? If so, which type and which patient?
Schnabel: Currently I would be very careful about the use of fish oil and the prescription of fish oil in either primary or secondary prevention. We will examine the studies for their content. There is a lot 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 a pretty impressive 25% risk reduction. The JELIS study, the Japanese EPA study, also had a risk reduction of around 20% with a pure EPA form of fish oil.
I don’t think I’ll go crazy and use it on all of my patients – and I haven’t – but I think there could still be some very high risk patients for whom an EPA-only drug might be helpful, especially those with high triglycerides.
The atrial fibrillation data really makes me pause. In my patients with paroxysmal atrial fibrillation and perhaps even other markers that indicate a high risk of atrial fibrillation, I personally would not 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 get another try to clear up this apple-to-orange comparison, and hopefully one that is just EPA versus a more neutral placebo is so we can settle the controversy.
Thank you for joining me for this interview, Renate. I hope you had a good AHA. Hope you all out there enjoyed the conversation. Thanks very much.
Schnabel: Thank you. It was a pleasure.
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