Low-dose omega-3 fatty acids offered no cardiovascular benefit over corn oil placebo in 2 randomized trials of high-risk patients, resurfacing old questions about why REDUCE-IT handled a favorable 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 individuals with high triglycerides however did increase new-onset atrial fibrillation (Afib).
New-onset Afib had actually also been shown to be elevated with icosapent ethyl in the REDUCE-IT trial, as initially reported in 2018
Because trial, the prescription fish oil item (consisting of 4 g pure EPA) minimized 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 actually failed to reveal such a benefit.
In OMEMI, a 1.8-g supplement integrating EPA and DHA also failed to enhance cardiovascular event rates, this time among elderly MI survivors in Norway. Once again, there was a signal of more new-onset Afib amongst 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 formula of omega-3 fatty acids, for greater bioavailability, made no difference 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 needing hospitalization over a typical 42 months was comparable between patients randomized to this prescription mix of EPA and DHA and those designated placebo (120%vs 12.2%, HR 0.99, 95%CI 0.90 -1.09).
This finding was consistent throughout primary and secondary avoidance groups, according to Steven Nissen, MD, of Cleveland Clinic, and STRENGTH partners reporting in JAMA
More GI unfavorable occasions were observed in the omega-3 group (247%) compared with 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 usage of this omega-3 fat formulation to lower significant negative cardiovascular events in high-risk clients,” the authors concluded.
STRENGTH included 13,078 statin-treated participants in 22 countries who had high cardiovascular danger, hypertriglyceridemia, and low levels of HDL cholesterol. These patients were randomized to 4 g Epanova daily or a corn oil placebo.
Mean age was 62.5 years, and women made up 35%of the mate.
Modification in plasma EPA in the omega-3 group was 2688%at 12 months, while the modification 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 event rates.
Triglycerides were minimized to a greater extent with omega-3 fats (-190%vs -0.9%, P P
STRENGTH’s was limited by its unknown generalizability to lower-risk groups.
Nevertheless, the trial restored questions surrounding REDUCE-IT’s choice of comparator and the theory that the addition of DHA is harmful to the advantages of pure EPA.
Unlike REDUCE-IT and its mineral oil placebo, STRENGTH revealed no unfavorable impacts 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 hypothesized to be a drug interaction in between statins and the mineral oil placebo, which might have given the treatment arm an unfair edge in clinical outcomes.
” REDUCE-IT would require to be done once again with a neutral control,” Nissen told MedPage Today
It is also unclear why blood EPA levels were “tightly connected” with cardiovascular outcomes because trial, however not in STRENGTH.
” It is possible that the particular solution of EPA makes a difference in the way that EPA disperses and imparts downstream tissue effects. Such distinctions might not be effectively caught 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 Medication in Baltimore.
REDUCE-IT lead detective Deepak Bhatt, MD, Miles Per Hour, of Brigham and Women’s Health center and Harvard Medical School, kept in mind that another trial, JELIS, had also revealed cardiovascular benefits with an EPA-only method.
” Emerging standard science information demonstrate that DHA may counter a few of the cardiovascular advantages of EPA, and that the solution of the preparation matters– not all omega-3 fats are developed equivalent,” he told MedPage Today
” Although it seems not likely 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 unlikely given the little incentive by manufacturer Amarin to do so, stated JAMA deputy editor Gregory Curfman, MD, in an accompanying note, pointing out Amarin’s loss of several crucial patents on icosapent ethyl and FDA’s approval of a generic alternative.
However, the FDA must need such a postmarketing scientific trial in patients at threat for cardiovascular events, Curfman preserved.
Icosapent ethyl won FDA approval for cardiovascular prevention in late 2019.
In the much smaller sized OMEMI trial, older individuals beginning a 1.8-mg omega-3 fat supplement right after surviving an MI did not have less subsequent cardiovascular events in the next 2 years.
In between people randomized to daily omega-3 fat supplementation (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 cardiac arrest hospitalization at 2 years happened at comparable rates (214%vs 20.0%, HR 1.08, 95%CI 0.82 -1.41).
Additionally, the 2 groups had the exact same 5.5%incidence of all-cause mortality (HR 1.01, 95%CI 0.
” Accordingly, our findings extend the lack of impact by mixed EPA/DHA to reduce cardiovascular danger,” the authors stated.
Major bleeding rates were comparable (at 10.7%vs 11.0%on placebo), and there were no major negative occasions.
However, the disadvantage 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 uncertain and perhaps counter to expectations. It might be too little a population, and should be considered in context of ESSENTIAL Rhythm results revealing no distinction of marine omega-3s after median 5.3 years typical follow-up on Afib occasions,” commented L. Kristin Newby, MD, of Duke University School of Medicine in Durham, North Carolina.
For now, Afib “appears to be a repeating side effect” of omega-3 treatments, stated Salim Virani, MD, PhD, of Baylor College of Medication in Houston. “We need to keep an eye on it.”
OMEMI was carried out at 4 sites in Norway.
They cohort represented a “very high-risk group,” according to the private investigators. Average age was 74 years, and 29%of research study participants were ladies. At standard, 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 permitted to continue with a small spoonful daily– approximately 600 mg EPA and DHA, according to the detectives.
” It is likewise worth noting that the standard median levels in our material (2.5%EPA and 5.6%DHA) are significantly higher than corresponding values from population research studies in the USA (0.5%EPA and 2.9%DHA), recommending higher background usage of n-3 PUFA in our Norwegian study population,” according to Kalstad and colleagues.
They reported great adherence amongst study participants, considered that mean 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 connect to less clients reporting extra omega-3 fatty acid supplements throughout the study.
Triglycerides decreased by an average -8.1%with the omega-3 supplement and increased by 5.1%with placebo ( P
A major constraint of OMEMI was that just over a quarter of evaluated patients were consisted of in the study. The trial also ended up being underpowered due to the fact that of a lower occasion rate than anticipated.
Nevertheless, OMEMI outcomes were “reasonably consistent” with current omega-3 trials in other populations revealing no benefit post-MI and irregular benefits in meta-analysis, Newby said.
” Given absence of benefit, a negative effects, and expense, omega-3 fatty acid dietary supplements must not be used at any dosage and needs to actively be deprescribed by physicians. Clients tend to like these supplements, but this study and numerous previous ones have actually likewise been negative,” according to Bhatt.
” Offered the present unpredictable state of knowledge, neither patients nor doctors can be positive that omega-3 fatty acids have any health advantages, yet in 2019 the global market for omega-3 fats reached $4.1 billion and is anticipated to double by 2025,” Curfman kept in mind.
OMEMI was supported by grants from Stein Erik Hagen Structure for Medical Heart Research Study, Olav Thon Foundation, and Tom Wilhelmsen Foundation.
Nissen reported getting grants from AstraZeneca, Novartis, Abbvie, Silence Rehabs, Medtronic, MyoKardia, Esperion, Eli Lily, Amgen, Novo Nordisk, Pfizer, Cerenis, and The Medicines Business.