The results of the STRENGTH and OMEMI studies published at the American Heart Association’s virtual scientific sessions showed that two formulations of omega-3 fatty acids did not reduce cardiovascular events in patients with elevated triglycerides and low HDL cholesterol. Steven Nissen, MD, chair of the STRENGTH Executive Committee, told MedPage Today that the results suggest that the REDUCE-IT study (of another omega-3 product) was false positive.
In this exclusive MedPage Today video, Dr. Deepak Bhatt of the Cardiovascular Center at Brigham and Women’s Hospital in Boston and REDUCE-IT’s lead researcher on the claim.
A transcript of his comments follows:
After the various experiments with omega-3 fatty acids were presented, there was much discussion. In fact, two different studies were presented. One was the STRENGTH study, a large cardiovascular outcome study that looked at a specific blend of omega-3 fatty acids, four grams of DHA per day [docosahexaenoic acid] and EPA [eicosapentaenoic acid]as well as some other fatty acids, and this study was negative – that is, there was no benefit from the drug.
It was a large, well-conducted study, and I have to congratulate the investigators. It was final in its results.
It also shows, I thought, something really interesting that may not have fully come out, that the drug significantly lowered triglyceride levels but did not reduce ischemic events, and I think this is an important break.
Although enough power was provided for events, there was no reduction in ischemic events, so I think there is an important message there. Not everything that necessarily reduces triglycerides will reduce cardiovascular risk. It’s kind of an old story where we look at surrogate marks and can sometimes be misled, so it’s an important message. The triglyceride story has yet to be cleared up.
There are other studies beginning or ongoing looking at other ways to lower triglycerides – in some cases in the same range as this drug and in some cases many times more reduced, some with the new RNA-based therapeutics, for example.
These studies will definitely answer whether triglyceride reduction per se is sufficient to reduce cardiovascular risk if some of these compounds produced are gross triglyceride reductions, or whether we have been misled by thinking about triglyceride as a modifiable risk factor, while it may be a risk factor – and we know it for sure – but perhaps one that is not modifiable.
Another well-conducted study was presented at this AHA, the OMEMI study, which examined 1.8 grams of a mixture of DHA and thus another omega-3 fatty acid study per day. This study was also negative, particularly for STEMI [ST-elevation myocardial infarction] Patient. Once again I thought that I am reasonably capable, but not a signal of any benefit.
In fact, both studies had an indication of harm – that is, a significant increase in the magnitude of the atrial fibrillation, and I would say, regardless of the statistics, an increase in the OMEMI study as well. I can argue about the P-value, but I think the investigators appropriately interpreted it as a real signal, so no benefit and some downside.
So two studies that were negative, but each very informative.
I think when you look at it in the larger context, this goes hand in hand with a lot of attempts with mixtures of EPA and DHA that were not positive. That was a pretty consistent story. Now there were a few exceptions when looking at subsets of some studies or individual endpoints – for example the ASCEND study. Vascular death was nominally significantly reduced, but the overall study was neutral.
The overall study was also neutral in the VITAL study. However, if you look at some subgroups or certain secondary endpoints, there was some evidence of positivity there, but overall, the studies largely failed to meet their primary endpoint.
There are two very notable exceptions, however. The REDUCE-IT study, which I featured as a late breaker at AHA 2018, and the study published in the New England Journal of Medicine described a large and significant reduction in cardiovascular events, including death from cardiovascular causes, with a given prescription Type of highly purified EPA, i.e. not a mixture of omega-3 fatty acids, but EPA or eicosapentaenoic acid. There that was four grams per day, so a high dose of pure EPA and a very positive study. There, too, an increase in atrial fibrillation was observed.
The other study that preceded it – it was also positive – also used EPA, the JELIS study published in The Lancet in 2007. Another well-conducted, important study, at 1.8 grams per day in a largely or fully Japanese population, showed a significant reduction in ischemic events. This was a higher baseline EPA population who received a lower dose of EPA than REDUCE-IT and still a positive study.
There were many differences between REDUCE-IT and JELIS, but one is particularly important in connection with many discussions that have emerged from the STRENGTH study and have to do with the placebo choice.
While we used a mineral oil placebo in REDUCE-IT – in smaller amounts, of course, a substance that is generally believed to be inert when used in that amount – they did not use placebo in the JELIS study. It was a so-called open-label study, randomly assigned, but not an actual placebo. Patients either received or did not receive the EPA, and the endpoints were assessed and blindly scored in this study.
This is what is called a probe design to minimize any type of preload. We hadn’t really counted on bias in a long-term study of the kind JELIS was. So two different EPA attempts that were positive and each used icosapent ethyl as the active ingredient. A lot of people don’t know that about JELIS.
But in this study there is no placebo in REDUCE-IT, a placebo, but both come to essentially the same place with a significant reduction in ischemic events, a relative risk reduction of 19% with the 1.8 grams of icosapent ethyl per day that can be used in JELIS and a relative risk reduction of 25% with the four grams per day that are used in REDUCE-IT, so actually a very nice coherent story.
It seems that, as is often the case in medicine, what we study matters in relation to the actual drug. In this case, not everything can be summed up as a class effect, since omega-3 fatty acids and their biology are very complex and omega-3 fatty acids can be very different. The doses, the exact omega-3 fatty acids and also the formulation.
Of course, the formulation is very important for any drug. This is possibly even more true of omega-3 fatty acids. Because if made, processed, or packaged in a way that oxidizes the omega-3 fatty acid, it can lose all potential biological benefits.
Really fascinating science from the AHA about omega-3 fatty acids, but seen in a bigger context, quite in line with what we’ve seen in previous studies.