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 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 occasions 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 initially reported in 2018

Because trial, the prescription fish oil item (containing 4 g pure EPA) minimized cardiovascular occasions more than mineral oil placebo did in statin-treated people with high triglycerides. Supplements used in previous trials (e.g., CRUCIAL, ASCEND) had failed to reveal such a benefit.

In OMEMI, a 1.8-g supplement integrating EPA and DHA likewise stopped working to enhance cardiovascular event rates, this time among elderly MI survivors in Norway. Once 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 calling for another trial on icosapent ethyl.

STRENGTH

A carboxylic acid formulation of omega-3 fatty acids, for higher 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 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 corresponded across primary and secondary prevention groups, according to Steven Nissen, MD, of Cleveland Center, and STRENGTH collaborators reporting in JAMA

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

” These findings do not support usage of this omega-3 fatty acid formulation to lower significant unfavorable cardiovascular occasions in high-risk patients,” 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 clients 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. Diabetes existed in 70%of the group. At baseline, mean 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 2688%at 12 months, while the modification 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 blood cell EPA or DHA concentrations after 12 months of treatment associated with subsequent cardiovascular event rates.

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

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

Reevaluating REDUCE-IT?

Nevertheless, the trial restored 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 exposed no negative impacts 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 actually been hypothesized to be a drug interaction in between statins and the mineral oil placebo, which may have given the treatment arm an unreasonable edge in clinical outcomes.

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

It is likewise unclear why blood EPA levels were “tightly connected” with cardiovascular outcomes in that trial, however not in STRENGTH.

” It is possible that the specific formula of EPA makes a distinction in the manner in which EPA distributes and imparts downstream tissue results. Such differences might not be sufficiently caught by measuring general plasma or serum concentrations of EPA,” according to an editorial by Roger Blumenthal, MD, and coworkers of Johns Hopkins University School of Medication in Baltimore.

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

” Emerging fundamental science data show that DHA may counter a few of the cardiovascular benefits of EPA, which the formulation of the preparation matters– not all omega-3 fats are created equivalent,” he told MedPage Today

” Although it appears not likely that the more modest increase in DHA balanced out the much larger boost in EPA, there are no ASCVD [atherosclerotic cardiovascular disease] result trials of DHA monotherapy to have confidence in its impact,” Blumenthal’s group composed.

The prospect of a new medical trial comparing icosapent ethyl’s pure EPA with corn oil is not likely given the little incentive by manufacturer Amarin to do so, stated JAMA deputy editor Gregory Curfman, MD, in an accompanying note, citing Amarin’s loss of numerous key patents on icosapent ethyl and FDA’s approval of a generic alternative.

However, the FDA must need such a postmarketing scientific trial in clients at threat for cardiovascular events, Curfman preserved.

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

OMEMI

In the much smaller sized OMEMI trial, older individuals beginning a 1.8-mg omega-3 fat supplement right after enduring an MI did not have less subsequent cardiovascular events in the next 2 years.

In between individuals randomized to day-to-day omega-3 fat 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 cardiac arrest hospitalization at 2 years took place at similar rates (214%vs 20.0%, HR 1.08, 95%CI 0.82 -1.41).

Moreover, the two groups had the exact same 5.5%incidence of all-cause mortality (HR 1.01, 95%CI 0.

” Appropriately, our findings extend the absence of effect by blended EPA/DHA to lower cardiovascular danger,” the authors stated.

Major bleeding rates were similar (at 10.7%vs 11.0%on placebo), and there were no severe adverse occasions.

However, the downside 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 result is uncertain and maybe counter to expectations. It might be too little a population, and must be thought about in context of ESSENTIAL Rhythm outcomes showing 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 “seems to be a repeating side effect” of omega-3 therapies, stated Salim Virani, MD, PhD, of Baylor College of Medication in Houston. “We require to keep an eye on it.”

OMEMI was performed at four sites in Norway.

They friend represented a “really high-risk group,” according to the investigators. Typical age was 74 years, and 29%of study individuals 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 individuals reported use of some omega-3 fatty acid supplement at baseline. They were enabled to continue with a small spoonful everyday– roughly 600 mg EPA and DHA, according to the private investigators.

” It is also worth keeping in mind that the standard median levels in our product (2.5%EPA and 5.6%DHA) are significantly higher than corresponding worths from population studies in the USA (0.5%EPA and 2.9%DHA), suggesting higher background intake of n-3 PUFA in our Norwegian research study population,” according to Kalstad and associates.

They reported excellent adherence amongst research study participants, given that average 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 might relate to less patients reporting extra omega-3 fatty acid supplementation throughout the study.

Triglycerides reduced 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 clients were included in the study. The trial also wound up being underpowered because of a lower occasion rate than expected.

Nonetheless, OMEMI outcomes were “fairly constant” with recent omega-3 trials in other populations showing no benefit post-MI and irregular advantages in meta-analysis, Newby stated.

” Offered absence of benefit, a side effect, and expense, omega-3 fatty acid dietary supplements need to not be utilized at any dose and ought to actively be deprescribed by doctors. Clients tend to like these supplements, however this research study and numerous prior ones have also been unfavorable,” according to Bhatt.

” Given the existing unsure state of understanding, neither clients nor doctors can be positive that omega-3 fatty acids have any health benefits, yet in 2019 the international market for omega-3 fats reached $4.1 billion and is anticipated 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 medication. Follow

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Disclosures

OMEMI was supported by grants from Stein Erik Hagen Structure for Clinical Heart Research, Olav Thon Structure, and Tom Wilhelmsen Foundation.

Nissen reported receiving grants from AstraZeneca, Novartis, Abbvie, Silence Rehabs, Medtronic, MyoKardia, Esperion, Eli Lily, Amgen, Novo Nordisk, Pfizer, Cerenis, and The Medicines Business.

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