New STRENGTH analysis revives the omega-3 debate

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“We believe that there is still great uncertainty as to whether these omega-3 fatty acids will actually benefit patients,” says Steven Nissen.

The researchers at STRENGTH have once again examined their data in more detail and once again questioned what the neutral result of their study means for the interpretation of other studies on omega-3 fatty acids, in particular by REDUCE-IT.

STRENGTH failed to show that an omega-3 carboxylic acid formulation containing both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – called Epanova (AstraZeneca) – reduced cardiovascular events in patients with elevated triglycerides and low HDL cholesterol. When the results were released in November 2020, Dr. Steven Nissen (Cleveland Clinic, OH), chair of the study executive committee, stated that the REDUCE-IT study – which was successful with icosapent ethyl (Vascepa; Amarin), an omega-3 formulation that contained purified EPA, was ” a false positive result ”.

The reasons for explaining the different results were differences in placebo, with REDUCE-IT using a mineral oil placebo associated with a certain risk and STRENGTH using a more neutral corn oil placebo. higher EPA values ​​achieved in REDUCE-IT; and possible damage from the DHA contained in the active ingredient tested in STRENGTH.

Last weekend, at the American College of Cardiology (ACC) 2021 virtual scientific session, Nissen presented results of a post-hoc analysis of STRENGTH to explore the latter two possibilities. This showed that the risk of MACE in patients with the highest plasma EPA levels was not reduced after 1 year or worsened in those with the highest plasma DHA levels.

Related to the increased risk of atrial fibrillation seen in STRENGTH, REDUCE-IT, and other fish oil studies, Nissen argued that it was not clear whether treatment with omega-3 fatty acids improves outcomes for patients and urged them more research to compare the effects of mineral oil versus corn oil and to compare purified EPA with other omega-3 fatty acid formulations.

“We believe that the reason that STRENGTH and REDUCE-IT showed different results is that we had different comparators,” Nissen repeated during a press conference at ACC. “Corn oil was neutral, and there was a lot of evidence that mineral oil wasn’t neutral, but it actually increased cardiovascular events. We therefore believe that there is still great uncertainty as to whether these omega-3 fatty acids will actually benefit patients. “

Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), REDUCE-IT’s lead researcher who was the panelist after Nissen’s presentation, had a different theory: “Alternatively, it could just be a different drug, different results.”

Sharp increase in EPA with no effect

For the post-hoc STRENGTH analysis, which was also published online in JAMA Cardiology, the examiners examined data from 10,382 study participants who had information on EPA and DHA levels after one year. They divided actively treated patients into tertiles with achieved omega-3 fatty acid levels.

Baseline characteristics were generally similar across tertile and placebo groups. The lipid measurements were also broadly similar, except that active treatment reduced triglycerides by about 19%, Nissen reported.

At 12 months, the mean upper-tertile plasma EPA level was 151 µg / ml, an increase of 443% from baseline. The mean plasma DHA level was 118 µg / ml, which corresponds to an increase of 68%.

There was no relationship between MACE and the upper tertile of either EPA achieved (adjusted HR 0.98; 95% CI 0.83-1.16) or DHA achieved (adjusted HR 1.02; 95% CI 0.86-1 , 20). Likewise, there were no significant correlations when considering changes in plasma EPA or DHA or the values ​​achieved or changes in EPA or DHA of the red blood cells.

Nissen recognized some limitations of this analysis, including its post-hoc nature, which means that it should be viewed as exploratory and hypothesizing. In addition, there was a moderate correlation between EPA and DHA levels, making it difficult to independently assess the relationship of each fatty acid to clinical outcomes, he said.

Still, Nissen claimed that these results suggest that it is not clear whether REDUCE-IT actually provides any benefit, especially given the fact that there are several other neutral studies in this area. “In these circumstances, I cannot recommend these drugs, especially given the significant increase in atrial fibrillation. I think we need more studies to answer the question,” he said. “Replication is important in the world of clinical trials, and the problem is that STRENGTH does not replicate the results of REDUCE-IT.”

“Proof is in the pudding”

Michael Miller, MD (University of Maryland Medical School, Baltimore), a member of the REDUCE-IT Steering Committee, noted that it is difficult to separate the effects of EPA from those of DHA in STRENGTH when looking at the different results from STRENGTH and REDUCE explained -ES. “You can’t separate DHA from EPA because they were correlated, so you lose some of the robust effect of EPA-only studies,” Miller explained.

He pointed to research suggesting that DHA has adverse effects on cell membranes and that it may have pro-oxidative and pro-inflammatory effects to explain why the entrapment of DHA could be a problem.

Miller, a member of the ACC Prevention Nutrition & Lifestyle Work Group, also backed down against Nissen’s claim that REDUCE-IT’s findings were not supported by other studies. JELISHe also showed that icosapent ethyl reduced cardiovascular events in patients with hypercholesterolemia. In addition, angiographic studies like EVAPORATE show that the drug slows the progression of atherosclerosis. “If you add DHA to the mix, you seem to lose that effect,” Miller said.

For practicing physicians trying to decide whether to use omega-3 fatty acid therapy for their patients, he says, “The proof is in the pudding. . . . As a clinician, I will continue to use what works. “Until the effects of EPA and DHA can be unraveled, he added,” I’ll go with the evidence, and the evidence is today with purified EPA like icosapent ethyl. “

Bhatt said that while STRENGTH did not show a relationship between omega-3 fatty acid levels and ischemic events, “one could simply conclude that the lack of a relationship in a negative study doesn’t mean much other than the specific drug studied didn’t work. “

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