Low-dose omega-3 fats provided no cardiovascular advantage over corn oil placebo in two randomized trials of high-risk clients, resurfacing old concerns about why REDUCE-IT handled 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 actually also been shown to be raised with icosapent ethyl in the REDUCE-IT trial, as first reported in 2018
In that trial, the prescription fish oil item (consisting of 4 g pure EPA) decreased cardiovascular events more than mineral oil placebo performed in statin-treated people with high triglycerides. Supplements utilized in prior trials (e.g., IMPORTANT, ASCEND) had failed to show such an advantage.
In OMEMI, a 1.8-g supplement combining EPA and DHA also stopped working to enhance cardiovascular event rates, this time amongst elderly MI survivors in Norway. Once again, there was a signal of more new-onset Afib amongst omega-3 fat receivers.
Presentation of STRENGTH and OMEMI at this year’s virtual conference 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 solution of omega-3 fats, for greater bioavailability, made no distinction in cardiovascular occasion rates in the STRENGTH trial, which was stopped early for futility.
The composite endpoint of cardiovascular death, MI, stroke, coronary revascularization, or unsteady angina requiring hospitalization over a typical 42 months was similar in between patients randomized to this prescription mix of EPA and DHA and those appointed placebo (120%vs 12.2%, HR 0.99, 95%CI 0.90 -1.09).
This finding corresponded throughout main and secondary prevention groups, according to Steven Nissen, MD, of Cleveland Clinic, and STRENGTH collaborators reporting in JAMA
More GI unfavorable occasions were observed in the omega-3 group (247%) compared to placebo-treated patients (147%). The previous 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 lower major adverse cardiovascular events in high-risk clients,” the authors concluded.
STRENGTH included 13,078 statin-treated participants in 22 countries who had high cardiovascular threat, hypertriglyceridemia, and low levels of HDL cholesterol. These clients were randomized to 4 g Epanova each day or a corn oil placebo.
Mean age was 62.5 years, and ladies made up 35%of the accomplice. Diabetes existed in 70%of the group. At standard, typical LDL cholesterol level was 75.0 mg/dL, triglycerides 240 mg/dL, and HDL cholesterol 36 mg/dL.
Modification in plasma EPA in the omega-3 group was 2688%at 12 months, while the change in DHA was 397%. Placebo was associated with declines of 10.5%and 6.9%, respectively.
In a post hoc exploratory analysis, neither plasma nor red cell EPA or DHA concentrations after 12 months of treatment correlated with subsequent cardiovascular occasion rates.
Triglycerides were minimized to a greater degree with omega-3 fats (-190%vs -0.9%, P P
STRENGTH’s was restricted by its unidentified generalizability to lower-risk groups.
However, the trial restored concerns surrounding REDUCE-IT’s option of comparator and the theory that the addition of DHA is damaging to the advantages of pure EPA.
Unlike REDUCE-IT and its mineral oil placebo, STRENGTH revealed no negative results on apolipoprotein B, LDL cholesterol, and inflammatory marker high level of 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 in between statins and the mineral oil placebo, which might have offered the treatment arm an unfair edge in medical outcomes.
” REDUCE-IT would require to be done again with a neutral control,” Nissen told MedPage Today
It is also uncertain why blood EPA levels were “firmly linked” with cardiovascular results in that trial, however not in STRENGTH.
” It is possible that the specific solution of EPA makes a distinction in the way that EPA disperses and imparts downstream tissue results. Such distinctions may not be effectively captured by determining basic plasma or serum concentrations of EPA,” according to an editorial by Roger Blumenthal, MD, and colleagues of Johns Hopkins University School of Medication in Baltimore.
REDUCE-IT lead investigator Deepak Bhatt, MD, MPH, of Brigham and Women’s Healthcare facility and Harvard Medical School, kept in mind that another trial, JELIS, had actually also revealed cardiovascular advantages with an EPA-only method.
” Emerging basic science information show that DHA might counter a few of the cardiovascular benefits of EPA, which the solution of the preparation matters– not all omega-3 fatty acids are created equivalent,” he told MedPage Today
” Although it seems unlikely that the more modest boost in DHA offset the much larger boost in EPA, there are no ASCVD [atherosclerotic cardiovascular disease] result trials of DHA monotherapy to have confidence in its effect,” Blumenthal’s group composed.
The possibility of a brand-new clinical trial comparing icosapent ethyl’s pure EPA with corn oil is not likely offered the little incentive by manufacturer Amarin to do so, stated JAMA deputy editor Gregory Curfman, MD, in an accompanying note, mentioning Amarin’s loss of several essential patents on icosapent ethyl and FDA’s approval of a generic option.
Nevertheless, the FDA must require such a postmarketing clinical trial in clients at threat for cardiovascular occasions, Curfman kept.
Icosapent ethyl won FDA approval for cardiovascular prevention in late 2019.
In the much smaller OMEMI trial, older individuals starting a 1.8-mg omega-3 fat supplement not long after enduring an MI did not have less subsequent cardiovascular events in the next 2 years.
In between people randomized to day-to-day omega-3 fatty acid supplements (930 mg EPA plus 660 mg DHA) vs placebo (corn oil), the composite endpoint of non-fatal severe MI, unscheduled revascularization, stroke, all-cause death, and heart failure hospitalization at 2 years happened at similar rates (214%vs 20.0%, HR 1.
Moreover, the 2 groups had the exact same 5.5%occurrence of all-cause mortality (HR 1.01, 95%CI 0.
” Appropriately, our findings extend the lack of impact by blended EPA/DHA to lower cardiovascular threat,” the authors said.
Major bleeding rates were comparable (at 10.7%vs 11.0%on placebo), and there were no major adverse occasions.
Nevertheless, the drawback for the 1.8-mg omega-3 supplement was its association with brand-new Afib (7.2%vs 4.0%, HR 1.84, 95%CI 0.
” The Afib outcome is unclear and possibly counter to expectations. It may be too small a population, and should be considered in context of VITAL Rhythm outcomes revealing no difference of marine omega-3s after mean 5.3 years average follow-up on Afib events,” commented L. Kristin Newby, MD, of Duke University School of Medicine in Durham, North Carolina.
For now, Afib “appears to be a recurring negative effects” of omega-3 treatments, said Salim Virani, MD, PhD, of Baylor College of Medicine in Houston. “We need to keep an eye on it.”
OMEMI was performed at 4 websites in Norway. Participants were 1,027 people ages 70 to 82 with a severe MI in the 2-8 weeks prior to registration. They were randomized to the omega-3 fatty acid supplement or placebo atop their standard secondary prevention treatments.
They cohort represented a “extremely high-risk group,” according to the detectives.
Over 40%of individuals reported usage of some omega-3 fatty acid supplement at standard. They were permitted to continue with a little spoonful everyday– roughly 600 mg EPA and DHA, according to the private investigators.
” It is likewise worth noting that the standard average levels in our product (2.5%EPA and 5.6%DHA) are especially higher than matching values from population studies in the USA (0.5%EPA and 2.9%DHA), recommending greater background usage of n-3 PUFA in our Norwegian study population,” according to Kalstad and coworkers.
They reported great adherence among research study individuals, considered that typical modification 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 might associate with fewer clients reporting extra omega-3 fatty acid supplementation throughout the research study.
Triglycerides decreased by an average -8.1%with the omega-3 supplement and increased by 5.1%with placebo ( P
A major restriction of OMEMI was that just over a quarter of evaluated clients were consisted of in the study. The trial also ended up being underpowered due to the fact that of a lower event rate than expected.
Nevertheless, OMEMI results were “reasonably consistent” with current omega-3 trials in other populations revealing no benefit post-MI and irregular advantages in meta-analysis, Newby stated.
” Provided lack of benefit, a side effect, and expense, omega-3 fat dietary supplements should not be utilized at any dosage and ought to actively be deprescribed by doctors. Clients tend to like these supplements, but this research study and a number of prior ones have also been unfavorable,” according to Bhatt.
” Given the current unsure state of knowledge, neither clients nor doctors can be positive that omega-3 fats have any health advantages, yet in 2019 the worldwide market for omega-3 fatty acids reached $4.1 billion and is expected to double by 2025,” Curfman noted.
STRENGTH was moneyed by AstraZeneca.
OMEMI was supported by grants from Stein Erik Hagen Structure for Scientific Heart Research, Olav Thon Structure, and Tom Wilhelmsen Foundation.
Nissen reported receiving grants from AstraZeneca, Novartis, Abbvie, Silence Therapies, Medtronic, MyoKardia, Esperion, Eli Lily, Amgen, Novo Nordisk, Pfizer, Cerenis, and The Medicines Business.
Kalstad, Blumenthal, and Curfman had no disclosures.