Anatomy of a fish tale: Evidence ‘weak’ for CV benefit with omega-3 supplementation
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Evidence is “weak” that eating fish can reduce risk for cardiovascular events, and data from multiple large trials suggest fish oil supplementation is CV neutral and may even increase risk for atrial fibrillation, according to a speaker.
A secondary analysis of the STRENGTH trial demonstrated that higher blood levels of eicosapentaenoic acid (EPA) 1 year after daily omega-3 carboxylic acid supplementation were not associated with lower CV risk among adults with hypertriglyceridemia and high risk for CVD, Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said during a presentation at the American Association of Clinical Endocrinology virtual meeting.
Data from STRENGTH, which compared 4 g daily omega-3 carboxylic acid with corn oil placebo, were similar to the neutral findings observed in large, lower-dose omega-3 fatty acid trials, like VITAL, ASCEND and ORIGIN. However, debate over omega-3 supplementation continues in the wake of the REDUCE-IT trial, presented in 2018, which showed a pharmaceutical-grade omega-3 fatty acid containing pure EPA, icosapent ethyl (Vascepa, Amarin), sharply reduced risk for ischemic events in a similar patient group.
Additionally, in multiple trials, including STRENGTH and REDUCE-IT, researchers observed higher incidence of new-onset atrial fibrillation in the omega-3 groups, Nissen said.
“We are left with a quandary, and clinicians have to decide what to do,” Nissen, also study chair for the STRENGTH trial, told Healio. “Putting this in the context of the very large increase in atrial fibrillation now seen in three trials — REDUCE-IT, STRENGTH and ONEMI — the question is, do any of these [fish oil] products produce more benefit than harm? I am unconvinced that they do.”
Comparing studies
As Healio previously reported, data from STRENGTH, first presented at the virtual American Heart Association Scientific Sessions in November, showed that administration of high-dose omega-3 carboxylic acid, a combination of EPA and docosahexaenoic acid (DHA), compared with corn oil placebo, did not reduce risk for the primary endpoint, a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization or unstable angina requiring hospitalization. The post hoc STRENGTH analysis, presented in May at the American College of Cardiology Scientific Session, showed that findings were unchanged when assessing participants in the highest tertile of EPA blood levels — those who saw a mean 443% increase. Similarly, the new analysis showed no evidence of harm among participants in the top tertile of DHA level.
The STRENGTH findings were in stark contrast to the REDUCE-IT trial, which demonstrated that icosapent ethyl, a pharmaceutical-grade omega-3 fatty acid containing EPA but not DHA, was superior to placebo for reducing risk for ischemic events in adults with hypertriglyceridemia at high CV risk.
Nissen and other researchers have suggested the placebo used could explain the difference. In REDUCE-IT, researchers used 4 g daily mineral oil placebo as the comparator, with significant adverse effects, Nissen said. At year 2 of REDUCE-IT, participants assigned mineral oil saw a mean 11.4% increase in LDL cholesterol and a mean 32.3% increase in high-sensitivity C-reactive protein. In STRENGTH, participants assigned corn oil saw a mean 1.1% decrease in LDL cholesterol and a mean 6% decrease high-sensitivity C-reactive protein.
“There is a huge adverse effect on lipids with mineral oil,” Nissen said. “When REDUCE-IT came along, I was skeptical from day 1 that is was a true positive result. Then I saw the lipid and inflammatory effects and was quickly convinced it was a false-positive study. The 32% increase in C-reactive protein in the mineral oil group is not trivial. Whether it is enough to drive the results, no one will ever be able to prove.”
“I don’t think we have the answer on fish oil, but I do not think REDUCE-IT can be accepted without replication of the trial using a neutral placebo,” Nissen said during his presentation.
Addressing mixed messages
Clinicians are now hearing two “fish tales,” Nissen said: That a pure EPA omega-3 fatty acid formulation used in REDUCE-IT is superior to combination EPA/DHA formulations like the one used in STRENGTH, and that DHA may counter some of the benefits of EPA, leading to the neutral CV findings in other trials.
Nissen disagrees.
“If EPA is beneficial, we should have seen something in those participants who saw huge EPA increases in STRENGTH,” Nissen told Healio. “EPA is EPA. We often hear that a certain version of a product has pleotropic effects, or some special benefit. In general, that has not panned out very well.”
Given the available data on risk for new-onset AF, Nissen said he “cannot justify” prescribing fish oil products to patients, apart from very specific circumstances.
“I do use the drug in people whose triglyceride level is above 500 mg/dL, because there is at least some reasonable evidence that [supplementation] might prevent pancreatitis,” Nissen told Healio. “That is a very small number of people. In the absence of that, I am not comfortable prescribing these drugs.”
“I’ll leave you with a little bit of a tongue-in-cheek comment,” Nissen said at the end of his presentation. “Forget about fish oil. Just use olive oil in your cooking and your salads.”
Perspective
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Usually, my one-liner to patients is that fish oil mixtures — those with EPA and DHA and especially over-the-counter supplements — have no CV benefit. This has been well proven now. Hence, I have been deprescribing these mixtures for people who might be taking them. I personally prescribe very limited fish oil in my practice for triglyceride lowering, only when my options are extremely limited. Fish oil of any kind does not seem to be of much benefit in marked hypertriglyceridemia (≥ 1000 mg/dL). That said, the REDUCE-IT trial certainly is striking in its CV results, and I do not think one can ignore it.
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Nissen SE. Omega-3 fatty acids and cardiovascular outcomes: Anatomy of a fish tale. Presented at: American Association of Clinical Endocrinology Annual Scientific and Clinical Conference; May 26-29, 2021 (virtual meeting).
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