Omega-3s Humbled by Corn Oil Placebo in Two Trials

Omega-3s Humbled by Corn Oil Placebo in Two Trials

Low-dose omega-3 fatty acids offered 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 outcome 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 occasions versus placebo in individuals with high triglycerides but did increase new-onset atrial fibrillation (Afib).

New-onset Afib had actually also been revealed to be raised with icosapent ethyl in the REDUCE-IT trial, as first reported in 2018

In that trial, the prescription fish oil item (containing 4 g pure EPA) lowered cardiovascular events more than mineral oil placebo did in statin-treated individuals with high triglycerides. Supplements used in prior trials (e.g., CRUCIAL, ASCEND) had actually stopped working to reveal such an advantage.

In OMEMI, a 1.8-g supplement combining EPA and DHA also stopped working 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 conference of the American Heart Association left some questioning the security of omega-3 fat supplements and requiring another trial on icosapent ethyl.

STRENGTH

A carboxylic acid solution of omega-3 fats, for greater bioavailability, made no distinction 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 unsteady angina needing hospitalization over a mean 42 months was similar in 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 across main and secondary avoidance groups, according to Steven Nissen, MD, of Cleveland Center, and STRENGTH partners reporting in JAMA

More GI adverse occasions were observed in the omega-3 group (247%) compared with placebo-treated patients (147%). The former likewise experienced more new-onset atrial fibrillation (2.2%vs 1.3%, HR 1.

” These findings do not support usage of this omega-3 fat formulation to minimize significant unfavorable cardiovascular occasions in high-risk patients,” the authors concluded.

STRENGTH consisted of 13,078 statin-treated participants in 22 nations 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 mate. Diabetes existed in 70%of the group. At baseline, 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 connected with decreases 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 associated with subsequent cardiovascular event rates.

Triglycerides were decreased to a higher extent with omega-3 fatty acids (-190%vs -0.9%, P

STRENGTH’s was limited by its unidentified generalizability to lower-risk groups.

Reconsidering REDUCE-IT?

Even so, the trial restored concerns surrounding REDUCE-IT’s choice of comparator and the theory that the addition of DHA is detrimental 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 may have offered the treatment arm an unfair edge in medical outcomes.

” REDUCE-IT would require to be done again with a neutral control,” Nissen informed MedPage Today

It is also uncertain why blood EPA levels were “tightly linked” with cardiovascular results because trial, but not in STRENGTH.

” It is possible that the particular formulation of EPA makes a distinction in the way that EPA distributes and imparts downstream tissue results. Such distinctions might not be properly caught by measuring general plasma or serum concentrations of EPA,” according to an editorial by Roger Blumenthal, MD, and associates of Johns Hopkins University School of Medicine in Baltimore.

REDUCE-IT lead investigator Deepak Bhatt, MD, MPH, of Brigham and Women’s Health center and Harvard Medical School, kept in mind that another trial, JELIS, had also revealed cardiovascular advantages with an EPA-only technique.

” Emerging fundamental science information demonstrate that DHA may counter some of the cardiovascular benefits of EPA, which the solution of the preparation matters– not all omega-3 fats are created equivalent,” he informed MedPage Today

” Although it appears unlikely that the more modest boost in DHA offset the much bigger increase in EPA, there are no ASCVD [atherosclerotic cardiovascular disease] result trials of DHA monotherapy to believe in its result,” 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 producer Amarin to do so, said JAMA deputy editor Gregory Curfman, MD, in an accompanying note, pointing out Amarin’s loss of a number of crucial patents on icosapent ethyl and FDA’s approval of a generic alternative.

However, the FDA should require such a postmarketing medical trial in clients at risk for cardiovascular events, Curfman preserved.

Icosapent ethyl won FDA approval for cardiovascular prevention in late 2019.

OMEMI

In the much smaller sized OMEMI trial, older people starting a 1.8-mg omega-3 fatty acid supplement soon after enduring an MI did not have less subsequent cardiovascular events in the next 2 years.

In between individuals randomized to everyday 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 (214%vs 20.0%, HR 1.

Furthermore, 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 result by mixed EPA/DHA to minimize cardiovascular threat,” the authors stated.

Significant bleeding rates were comparable (at 10.7%vs 11.0%on placebo), and there were no severe unfavorable events.

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 0.98 -3.45). This finding did not reach analytical significance, it is “of interest” offered the senior client population already at high danger of Afib, Kalstad and associates said.

” The Afib outcome is unclear and possibly counter to expectations. It might be too small a population, and ought to be considered in context of IMPORTANT Rhythm outcomes showing no difference of marine omega-3s after typical 5.3 years mean follow-up on Afib occasions,” commented L. Kristin Newby, MD, of Duke University School of Medication in Durham, North Carolina.

For now, Afib “appears to be a repeating negative effects” of omega-3 treatments, stated Salim Virani, MD, PhD, of Baylor College of Medicine in Houston. “We require to keep an eye on it.”

OMEMI was performed at 4 sites in Norway.

They associate represented a “really high-risk group,” according to the private investigators.

Over 40%of people reported usage of some omega-3 fatty acid supplement at standard. They were enabled to continue with a little spoonful everyday– approximately 600 mg EPA and DHA, according to the private investigators.

” It is also worth noting that the standard median levels in our material (2.5%EPA and 5.6%DHA) are significantly greater than corresponding worths from population studies in the USA (0.5%EPA and 2.9%DHA), recommending higher background usage of n-3 PUFA in our Norwegian research study population,” according to Kalstad and colleagues.

They reported great adherence among research study participants, given that average 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 connect to fewer clients reporting extra omega-3 fatty acid supplements over the course of the research study.

Triglycerides decreased by a typical -8.1%with the omega-3 supplement and increased by 5.1%with placebo ( P

A major limitation of OMEMI was that simply over a quarter of screened patients were included in the research study. The trial likewise ended up being underpowered because of a lower occasion rate than expected.

Nonetheless, OMEMI outcomes were “reasonably constant” with recent omega-3 trials in other populations revealing no advantage post-MI and inconsistent advantages in meta-analysis, Newby said.

” Provided lack of benefit, an adverse effects, and cost, omega-3 fatty acid dietary supplements should not be utilized at any dose and needs to actively be deprescribed by doctors. Patients tend to like these supplements, but this study and numerous prior ones have actually likewise been unfavorable,” according to Bhatt.

” Given the existing uncertain state of knowledge, neither patients nor physicians can be confident that omega-3 fats have any health advantages, yet in 2019 the international market for omega-3 fats reached $4.1 billion and is expected to double by 2025,” Curfman kept in mind.

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    Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow

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Disclosures

STRENGTH was funded 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.

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