Low-dose omega-3 fatty acids offered no cardiovascular benefit over corn oil placebo in two randomized trials of high-risk patients, resurfacing old questions about why REDUCE-IT managed a positive result with icosapent ethyl (Vascepa).
In the STRENGTH trial, prescription omega-3 carboxylic acids (Epanova), a mix of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), didn’t lower cardiovascular events versus placebo in people with high triglycerides but did increase new-onset atrial fibrillation (Afib).
New-onset Afib had also been shown to be elevated with icosapent ethyl in the REDUCE-IT trial, as first reported in 2018.
In that trial, the prescription fish oil product (containing 4 g pure EPA) reduced cardiovascular events more than mineral oil placebo did in statin-treated people with high triglycerides. Supplements used in prior trials (e.g., VITAL, ASCEND) had failed to show such a benefit.
In OMEMI, a 1.8-g supplement combining EPA and DHA also failed to improve cardiovascular event rates, this time among elderly MI survivors in Norway. Again, there was a signal of more new-onset Afib among omega-3 fatty acid recipients.
Presentation of STRENGTH and OMEMI at this year’s virtual meeting of the American Heart Association left some questioning the safety of omega-3 fatty acid supplements and calling for another trial on icosapent ethyl.
A carboxylic acid formulation of omega-3 fatty acids, for greater bioavailability, made no difference in cardiovascular event rates in the STRENGTH trial, which was stopped early for futility.
The composite endpoint of cardiovascular death, MI, stroke, coronary revascularization, or unstable angina requiring hospitalization over a median 42 months was similar between patients randomized to this prescription mix of EPA and DHA and those assigned placebo (12.0% vs 12.2%, HR 0.99, 95% CI 0.90-1.09).
This finding was consistent across primary and secondary prevention groups, according to Steven Nissen, MD, of Cleveland Clinic, and STRENGTH collaborators reporting in JAMA.
More GI adverse events were observed in the omega-3 group (24.7%) compared with placebo-treated patients (14.7%). The former also experienced more new-onset atrial fibrillation (2.2% vs 1.3%, HR 1.69, 95% CI 1.29-2.21).
“These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients,” the authors concluded.
STRENGTH included 13,078 statin-treated participants in 22 countries who had high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol. These patients were randomized to 4 g Epanova per day or a corn oil placebo.
Mean age was 62.5 years, and women comprised 35% of the cohort. Diabetes was present in 70% of the group. At baseline, median LDL cholesterol level was 75.0 mg/dL, triglycerides 240 mg/dL, and HDL cholesterol 36 mg/dL.
Change in plasma EPA in the omega-3 group was +268.8% at 12 months, while the change in DHA was +39.7%. Placebo was associated with decreases of 10.5% and 6.9%, respectively.
In a post hoc exploratory analysis, neither plasma nor red blood cell EPA or DHA concentrations after 12 months of treatment correlated with subsequent cardiovascular event rates.
Triglycerides were reduced to a greater extent with omega-3 fatty acids (-19.0% vs -0.9%, P<0.001). LDL cholesterol increased by 1.2% in the omega-3 group but fell 1.1% the corn oil group (P<0.001).
STRENGTH’s was limited by its unknown generalizability to lower-risk groups.
Even so, the trial revived questions surrounding REDUCE-IT’s choice of comparator and the theory that the addition of DHA is detrimental to the benefits of pure EPA.
Unlike REDUCE-IT and its mineral oil placebo, STRENGTH revealed no adverse effects on apolipoprotein B, LDL cholesterol, and inflammatory marker high sensitivity C-reactive protein levels in its corn oil placebo group, according to Nissen’s group.
These observations in REDUCE-IT had been speculated to be a drug interaction between statins and the mineral oil placebo, which might have given the treatment arm an unfair edge in clinical outcomes.
“REDUCE-IT would need to be done again with a neutral control,” Nissen told MedPage Today.
It is also unclear why blood EPA levels were “tightly linked” with cardiovascular outcomes in that trial, but not in STRENGTH.
“It is possible that the specific formulation of EPA makes a difference in the way that EPA distributes and imparts downstream tissue effects. Such differences may not be adequately captured by measuring general plasma or serum concentrations of EPA,” according to an editorial by Roger Blumenthal, MD, and colleagues of Johns Hopkins University School of Medicine in Baltimore.
REDUCE-IT lead investigator Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School, noted that another trial, JELIS, had also shown cardiovascular benefits with an EPA-only approach.
“Emerging basic science data demonstrate that DHA may counter some of the cardiovascular benefits of EPA, and that the formulation of the preparation matters – not all omega-3 fatty acids are created equal,” he told MedPage Today.
“Although it seems unlikely that the more modest increase in DHA offset the much larger increase in EPA, there are no ASCVD [atherosclerotic cardiovascular disease] outcome trials of DHA monotherapy to have confidence in its effect,” Blumenthal’s group wrote.
The prospect of a new clinical trial comparing icosapent ethyl’s pure EPA with corn oil is unlikely given the little incentive by manufacturer Amarin to do so, said JAMA deputy editor Gregory Curfman, MD, in an accompanying note, citing Amarin’s loss of several key patents on icosapent ethyl and FDA’s approval of a generic alternative.
Nevertheless, the FDA should require such a postmarketing clinical trial in patients at risk for cardiovascular events, Curfman maintained.
Icosapent ethyl won FDA approval for cardiovascular prevention in late 2019.
In the much smaller OMEMI trial, older people starting a 1.8-mg omega-3 fatty acid supplement soon after surviving an MI did not have fewer subsequent cardiovascular events in the next 2 years.
Between people randomized to daily omega-3 fatty acid supplementation (930 mg EPA plus 660 mg DHA) vs placebo (corn oil), the composite endpoint of non-fatal acute MI, unscheduled revascularization, stroke, all-cause death, and heart failure hospitalization at 2 years occurred at similar rates (21.4% vs 20.0%, HR 1.08, 95% CI 0.82-1.41).
Moreover, the two groups had the same 5.5% incidence of all-cause mortality (HR 1.01, 95% CI 0.60-1.71), according to Are Kalstad, MD, of Oslo University Hospital in Norway. His group’s study was simultaneously published in Circulation.
“Accordingly, our findings extend the lack of effect by mixed EPA/DHA to reduce cardiovascular risk,” the authors said.
Major bleeding rates were similar (at 10.7% vs 11.0% on placebo), and there were no serious adverse events.
However, the disadvantage for the 1.8-mg omega-3 supplement was its association with new Afib (7.2% vs 4.0%, HR 1.84, 95% CI 0.98-3.45). Although this finding did not reach statistical significance, it is “of interest” given the elderly patient population already at high risk of Afib, Kalstad and colleagues said.
“The Afib result is unclear and perhaps counter to expectations. It may be too small a population, and should be considered in context of VITAL Rhythm results showing no difference of marine omega-3s after median 5.3 years median follow-up on Afib events,” commented L. Kristin Newby, MD, of Duke University School of Medicine in Durham, North Carolina.
For now, Afib “seems to be a recurring side effect” of omega-3 therapies, said Salim Virani, MD, PhD, of Baylor College of Medicine in Houston. “We need to keep an eye on it.”
OMEMI was conducted at four sites in Norway. Participants were 1,027 people ages 70 to 82 with an acute MI in the 2-8 weeks prior to enrollment. They were randomized to the omega-3 fatty acid supplement or placebo atop their standard secondary prevention therapies.
They cohort represented a “very high-risk group,” according to the investigators. Median age was 74 years, and 29% of study participants were women. At baseline, average LDL and HDL cholesterol levels were 76 mg/dL and 49.5 mg/dL, respectively. Mean triglycerides were 111.4 mg/dL.
Over 40% of people reported use of some omega-3 fatty acid supplement at baseline. They were allowed to continue with a small spoonful daily — approximately 600 mg EPA and DHA, according to the investigators.
“It is also worth noting that the baseline median levels in our material (2.5% EPA and 5.6% DHA) are notably higher than corresponding values from population studies in the USA (0.5% EPA and 2.9% DHA), suggesting higher background consumption of n-3 PUFA in our Norwegian study population,” according to Kalstad and colleagues.
They reported good adherence among study participants, given that median change in EPA and DHA was +87% and +16%, respectively, with the supplement. The placebo group had EPA and DHA fall by 13% and 8%, which may relate to fewer patients reporting additional omega-3 fatty acid supplementation over the course of the study.
Triglycerides decreased by a median -8.1% with the omega-3 supplement and increased by 5.1% with placebo (P<0.001). LDL cholesterol was generally unchanged in both groups.
A major limitation of OMEMI was that just over a quarter of screened patients were included in the study. The trial also wound up being underpowered because of a lower event rate than expected.
Nonetheless, OMEMI results were “reasonably consistent” with recent omega-3 trials in other populations showing no benefit post-MI and inconsistent benefits in meta-analysis, Newby said.
“Given lack of benefit, a side effect, and cost, omega-3 fatty acid dietary supplements should not be used at any dose and should actively be deprescribed by physicians. Patients tend to like these supplements, but this study and several prior ones have also been negative,” according to Bhatt.
“Given the current uncertain state of knowledge, neither patients nor physicians can be confident that omega-3 fatty acids have any health benefits, yet in 2019 the global market for omega-3 fatty acids reached $4.1 billion and is expected to double by 2025,” Curfman noted.
STRENGTH was funded by AstraZeneca.
OMEMI was supported by grants from Stein Erik Hagen Foundation for Clinical Heart Research, Olav Thon Foundation, and Tom Wilhelmsen Foundation.
Nissen reported receiving grants from AstraZeneca, Novartis, Abbvie, Silence Therapeutics, Medtronic, MyoKardia, Esperion, Eli Lily, Amgen, Novo Nordisk, Pfizer, Cerenis, and The Medicines Company.
Kalstad, Blumenthal, and Curfman had no disclosures.