Steven Nissen argues that REDUCE-IT produced a “false-positive” result. But Deepak Bhatt, who studies PI, calls vocalism “ridiculous”.
(Update) The full results of the strength test confirm what has been known since the study Closed for futility Back in January: A carboxylic acid manufacture of omega-3 fatty acids (Apanova; AstraZeneca) does not reduce cardiovascular events in patients with elevated triglycerides and low HDL cholesterol.
But Strength’s Executive Committee Chairman Steven Nissen, MD (Cleveland Clinic, OH), argues that the negative test results have far-reaching effects, which were reported and simultaneously published during the Virtual American Heart Association 2020 scientific sessions Were. Jama.
“We believe that strength indicates that REDUCE-IT is a false-positive result. Fish oil has no effect on cardiovascular outcomes, as shown in other tests. REDUCE-IT is positive we think Because it uses a negative control instead of a neutral control, ”Nissen told TCTMD.
REDUCE-IT showed that another omega-3 fatty acid formulation — isosapant ethyl (Wasepa; amarin) —cat MACE by a relative compared to a placebo pill containing 25% mineral oil.
We believe that strength indicates that REDUCE-IT is a false-positive result. Steven Nissen
And this is a problem, Nissen said, because mineral oil in REDUCE-IT had a pro-inflammatory effect, which increased the treatment benefits seen in the trial. They also pointed to a 10.2% increase in LDL cholesterol, a 7.8% increase in apolipoprotein B, and a 32% increase in high-sensitivity C-reactive protein (hsCRP) in the placebo arm. This did not happen with a placebo in the strength trial, which included corn oil.
“I don’t think we can believe that fish oil is beneficial until REDUCE-IT is replicated with neutral controls like corn oil,” Nissan said.
The principal investigator of STRENGHT a. Michael Linkoff, MD (Cleveland Clinic), who presented the results today, “in reference to the increased risk of atrial fibrillation in this and other trials of omega-3 fatty acids.” [raise] A question about whether there is a net gain or loss with any omega-3 fatty acid preparation. “
But REDUCE-IT’s chief investigator, Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston), emphasized the criticisms of his test. For TCTMD, he highlighted the differences between the fish oil formulations used in the two tests. Echosapent ethyl, used in REDUCE-IT, is a pure form of eicosapentanoic acid (EPA), while Epanova, used in strength, is a mixture of EPA and docosaheleaenoic acid (DHA). Research has shown that EPA stabilizes cell membranes and DHA destabilizes them, meaning that DHA in Epanova can counteract the beneficial effects of EPA, explaining the results of the discrepancy test, Bhatt said.
“Not all omega-3 fatty acids are created equal. They have different physico-chemical properties, different biochemical properties, and therefore different conditions may have different effects on human health. “Even if skeptics are not convinced by that argument, he said, they should remember that alasipad was the first test of ethyl at low doses, it also showed a significant reduction in cardiac events. . In JELIS Testing, treatment reduced the incidence of a major relative by 19%.
Bhatt said, “For the prevention and treatment of heart, I think the REDUCE-IT Executive Committee and leadership team are confident that the results are quite robust and robust.”
Futility of Strength
Strength, conducted at 686 sites in 22 countries, included 13,078 statin-treated patients with high risk for CVD or triglycerides (180 to 500 mg / dL) and low HDL cholesterol (<42 mg / dL) for men and < 47 mg / dL for women). Participants were randomized to a carboxylic acid formulation of omega-3 fatty acids in corn oil placebo or apanova by combining EPA and DHA given at doses of 4 g / day. This formulation is very well absorbed, providing high levels of EPA and modest levels of DHA, Nissen said.
Active treatment was associated with a 268.8% increase in median plasma EPA levels – from 21.0 μg / mL at baseline level to 89.6 μg / mL at 1 year. There was a 19% drop in triglycerides (239 to 191 mg / dL) and a 20% decrease in hCRPP (2.13 to 1.69 mg / L).
However, through an average follow-up of 42.0 months, Ipanova did not reduce the risk of hospitalization for CV death, MI, coronary revascularization or unstable angina, the primary overall endpoint (12.0% vs. 12 %%); HR 0.99; 95% CI 0.90–1.09). It is the primary endpoint similar to REDUCE-IT.
Consistent with REDUCE-IT, fish oil treatment increased the risk of new onset-fiber (2.2% vs. 1.3%; HR 1.69; 95% CI 1.29–2.21). There was also a higher rate of GI adverse events (24.7% vs. 14.7%).
A tale of two trials
In a discussion on how to mix these results with the people of REDUCE-IT, Lincoff noted that the increase in EPA levels was about 45% higher in REDUCE-IT than in STRPATH, however, “This magnitude of difference seems insufficient to explain the completely different results of the two tests.” In addition, treatment in both trials resulted in a decrease in triglycerides of about 19%, suggesting similar biochemical effects, Linoloff said.
Even among participants who achieved the highest levels of EPA in strength, Nissan reported that there was no sign of benefit from active treatment. And that means, they argued that REDUCE-IT incorrectly demonstrated CV benefits where none could exist. “I think it is very unfortunate that REDUCE-IT, with all the pomp that it has got, is not really a positive test. And Strength shows us that “
But other commentators were not so sure. Karol Watson, MD (University of California, Los Angeles) stated that the negative strength results were surprising in light of REDUCE-IT. But there were differences between the tests, she noted, pointing to the inclusion of DHA in the manufacture of fish oil used in Strength, for one. He acknowledged the debate about the potential pitfalls of the mineral oil placebo used in REDUCE-IT, but did not think it would be enough to explain completely different test results. “We all just have to guess what would have happened if they used corn oil or olive oil or any other comparator. We don’t know right now, “Watson said. “But the REDUCE-IT results were so positive that it is difficult. . . Imagine all that profit goes away. “
I think at a certain point it is ridiculous not to believe anything. Deepak Bhatt
Salim Virani, MD, PhD (Baylor College of Medicine, Houston, TX) would not even go so far that Strength’s neutral result indicated that REDUCE-IT provided a false-positive result. He considered three main issues to list when it comes to comparing tests: formulations, placebo, and test populations.
Maybe EPA-only formulations are better than people with EPA and DHA, he said. And perhaps the impact of mineral oil explained the gains in REDUCE-IT, although “probably not when you have such a big risk,” Virani said. “Could he contribute?” Probably so. “
Virani, chair of the Prevention Section and Leadership Council of the American College of Cardiology, then considering the trial population, suggests that a higher proportion of REDUCE-IT participants had established CAD (71% vs. 56%). A high-risk patient population in REDUCE-IT, he said, is reflected in the rate of primary endpoint in the two trials’ placebo arms – 22.0% in REDUCE-IT and 12.2% in STRENGTH. Virani said, “The population at high risk may be where these triglyceride risk-based therapies work.”
So before coming to conclusions about false-positive test results, the community needs to be considerate and take time to study the nuanced differences between the tests, he said, noting that REDUCE-IT results have many endings The points were strong and consistent with and following the positive findings of JELIS.
Nissen acknowledged that the US Food and Drug Administration specifically examined the effect of mineral oil placebo on the results of REDUCE-IT, but “they were not able to demonstrate without doubt that REDUCE-IT was a false-positive.” ” Agency approved Prestigious Ethics in December 2019.
“I think it was a mistake and I don’t think fish oil is beneficial,” Nisen said. “We think our public health obligation is to take it out there and tell people, because as you know this EPA drug is being advertised on television, they have 800 delegates to push the drug , And we don’t think that is the right answer. “
Linkoff said he is not routinely prescribing omega-3 fatty acids to his patients, except in those with high levels of triglycerides (> 500 mg / dL), saying this is disputed. Whether “risk and benefit are favorable”. Ratio. “In response to a question in a press briefing, he said that patients should be warned about the risk of A-fib when taking omega-3 fatty acids.
For Bhatt, the answer is clear: “In two separate independent trials, icosapept ethyl showed a significant reduction in ischemic events. So I think at a certain point it is ridiculous not to believe anything. And I think the story for EPA is extremely strong at this point and the data is growing. “