New STRENGTH Analysis Revives Omega-3 Debate
“We think there is still a lot of uncertainty as to whether these omega-3 fatty acids actually benefit patients,” says Steven Nissen.
Looking further into their data, the STRENGTH investigators once again questioned the significance of their trial’s neutral result when it comes to interpreting other studies on omega-3 fatty acids, in particular REDUCE-IT.
STRENGTH has not shown that an omega-3 carboxylic acid formulation containing both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – called Epanova (AstraZeneca) – reduces cardiovascular events in patients patients with high triglycerides and low HDL cholesterol. When the results were published in November 2020, Steven Nissen, MD (Cleveland Clinic, OH), chairman of the trial executive, said this indicated that the REDUCE-IT trial – which was successful with the The icosapent ethyl (Vascepa; Amarin), an omega-3 formulation containing purified EPA – was “a false positive result”.
The reasons given for the diverging results were differences in placebo, with REDUCE-IT using a mineral oil placebo associated with some risk and FORCE using a more neutral corn oil placebo; higher EPA levels in REDUCE-IT; and the possible damage of DHA included in the agent tested in STRENGTH.
Last weekend, at the 2021 American College of Cardiology (ACC) Virtual Science Session, Nissen presented the results of a post hoc analysis of STRENGTH to address the latter two possibilities, demonstrating that the risk of MACE was not reduced in patients with the highest plasma EPA levels. at 1 year or worse in those with the highest plasma DHA levels.
Against the background of the increased risk of atrial fibrillation seen in the STRENGTH, REDUCE-IT, and other fish oil trials, Nissen argued that it is not clear whether omega-fatty acid treatment 3 improves patient outcomes, calling for more research to compare the effects of mineral oil versus corn oil and compare purified EPA with other formulations of omega-3 fatty acids.
“We believe that the reason STRENGTH and REDUCE-IT showed different results is that we had different comparators,” Nissen repeated during a press briefing at the ACC. “Corn oil was neutral, and there was plenty of evidence that mineral oil was not neutral, but it actually increased cardiovascular events. We therefore believe that there is still a lot of uncertainty as to whether these omega-3 fatty acids actually benefit patients.
REDUCE-IT principal investigator Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), who was the commentator after Nissen’s presentation, had another theory: “Otherwise it could just be a drug. different, different results. “
Large increases in EPA, no effects
For the post hoc STRENGTH analysis, published simultaneously online at JAMA Cardiology, investigators looked at data from 10,382 trial participants who had information about EPA and DHA levels at 1 year. They divided the actively treated patients into tertiles of achieved omega-3 fatty acid levels.
Baseline characteristics were generally similar between the tertiles and the placebo group. The lipid readings were also broadly similar, except the active treatment lowered triglycerides by about 19%, Nissen reported.
At 12 months, the median plasma EPA level in the upper tertile was 151 µg / mL, an increase of 443% from baseline. The median plasma DHA level was 118 µg / mL, an increase of 68%.
There was no relationship between MACE and the highest tertile of 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 relationships when examining changes in plasma EPA or DHA, or achieved levels or changes in red blood cells EPA or DHA.
Nissen recognized some limitations of this analysis, including the post hoc nature, which means that it should be viewed as exploratory and speculative. Additionally, there was a moderate correlation between EPA and DHA levels, complicating independent assessment of how each fatty acid relates to clinical outcomes, he said.
Nonetheless, Nissen argued that these results indicate that it is not clear whether there was actually a benefit to REDUCE-IT, especially since there are several other neutral trials in this space. “Under these circumstances, I cannot recommend giving these drugs, especially given the fairly substantial increase in atrial fibrillation, so I think we need more trials to answer the question,” he said. he stressed. “Replication is important in the world of clinical trials, and the problem is that STRENGTH does not replicate the results of REDUCE-IT.”
‘The proof is in the pudding’
REDUCE-IT Steering Committee member Michael Miller, MD (University of Maryland School of Medicine, Baltimore) focused on the difficulty of separating the effects of EPA from those of DHA in FORCE by explaining the disparate results of STRENGTH and REDUCE. -HE. “You can’t separate DHA from EPA because they were correlated, so you lose some of the robust effect of studies on EPA alone,” Miller explained.
He pointed to research indicating that DHA has adverse effects on cell membranes and suggesting that it may have prooxidant and pro-inflammatory effects as to why inclusion of DHA might be a problem.
Miller, a member of the ACC Prevention Nutrition & Lifestyle working group, also rebuffed Nissen’s claim that the results of REDUCE-IT are not supported by other trials. I READ, he noted, also showed that icosapent ethyl reduced cardiovascular events in patients with hypercholesterolemia. In addition, angiographic studies such as EVAPORATE show that the drug slows the progression of atherosclerosis. “When you put DHA into the mix, you seem to lose that effect,” Miller said.
His takeaway for medical practitioners trying to decide whether or not to use omega-3 fatty acid therapy for their patients is that “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 disentangled, he added, “I’m going to accept the evidence, and the evidence today is with purified EPA, like icosapent ethyl.”
Bhatt said that even though STRENGTH did not show a relationship between omega-3 fatty acid levels and ischemic events, “one could just conclude that the lack of a relationship in a negative trial doesn’t tell us much. something other than the specific drug. studied did not work.