Outcomes of the REDUCE-IT trial recommended that icosapent ethyl lowers the chance for ischemic occasions amongst sufferers with excessive triglycerides regardless of statin use — however instantly, controversy swirled.

The prescription product (Vascepa), consisting of a “extremely purified” type of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 as ushering in “the daybreak of a brand new period” in heart problems (CVD) prevention that “ought to undoubtedly change follow going ahead,” in accordance with REDUCE-IT’s lead writer Deepak L. Bhatt, MD, previously of Brigham and Girls’s Hospital in Boston and now Director of the Mount Sinai Coronary heart Heart in New York Metropolis.

Nonetheless, skeptics questioned why the outcomes differed from most earlier trials of fish oil that confirmed no profit. Was it as a result of excessive dose of EPA: 4 g/each day vs 1 g each day in earlier trials with fish oil capsules? Was it the completely different formulation of purified EPA vs extra frequent combos of EPA plus docosahexaenoic acid (DHA)? Or, as recommended by Steven Nissen, MD, chief educational officer of Cleveland Clinic’s Coronary heart and Vascular Institute and others, was it as a result of adverse results of the mineral oil placebo, given the numerous will increase in low-density lipoprotein ldl cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) seen within the management group?  

“Not All Omega-3s Created Equal”

Commenting not too long ago for theheart.org | Medscape Cardiology, Bhatt mentioned, “I believe there’s confusion within the discipline. It is a problem when only one drug in a category seems to be good and every thing else in that class seems to be unhealthy. That in itself can breed some skepticism. Additionally, not everybody all the time embraces advances. Some folks produce other causes to impugn datasets; for instance, it may very well be as a result of they’re working competing trials with competing medication.”

Dr Deepak Bhatt presenting REDUCE-IT on the AHA Scientific Classes 2018.

REDUCE-IT enrolled greater than 8000 sufferers at excessive CV danger regardless of statin remedy, and randomly assigned them to 2 g of EPA twice each day or the mineral oil placebo. Though the outcomes confirmed a 25% discount within the charge of CV occasions within the EPA group, there was additionally an elevated danger of atrial fibrillation amongst these taking EPA after a median of 4.9 years follow-up.

Bhatt famous that Amarin, which manufactures Vascepa, is actually a one-drug firm, and its inventory worth relies on the product. When the trial outcomes have been launched, he mentioned, “There have been folks within the investor world that needed the inventory worth to go up or needed it to go down, they usually have been alternately hyping or disparaging the info in each instances, typically inappropriately and excessively, which created noise across the science.”

The actual fact is, he mentioned, “not all omega-3 fatty acids are created equal. There are variations between dietary supplements and prescription medicines, and throughout the prescription medicines, variations between pure EPA and the mixtures of EPA and DHA.”

Bhatt added that different trials additionally confirmed constructive outcomes. He pointed to the JELIS trial, printed in 2007, which confirmed a 19% discount in main antagonistic CV occasions with a 1.8-g each day EPA dose.

Extra not too long ago, RESPECT-EPA was introduced on the American Coronary heart Affiliation Scientific Classes 2022. That research had methodological points and was underpowered, but it surely did counsel a doable good thing about EPA in lowering CV occasions in sufferers with power coronary artery illness who have been taking statins. “Wanting on the totality of proof, I believe it is fairly clear there’s CV profit,” Bhatt mentioned.

Placebo Results?

Considerations in regards to the mineral oil placebo solid doubt on that profit. Desk 4 of the complement accompanying REDUCE-IT’s publication within the New England Journal of Drugs reveals vital will increase of non-HDL ldl cholesterol, LDL-C, apolipoprotein B, and hsCRP within the management group.

Dr Jane Armitage

Jane Armitage, MBBS, a professor of Medical Trials and Epidemiology, Medical Trial Service Unit at Oxford College, United Kingdom, mentioned in an interview: “I used to be stunned by the backlash and on the time felt that it was unlikely that the mineral oil was the issue. However the dimension of profit was nonetheless out of kilter.”

“Two additional items of proof have influenced my ideas since then,” she mentioned. One is the dearth of impact of excessive doses of fish oils within the STRENGTH trial. STRENGTH examined 4 g of omega-3 oil containing a combination of EPA and DHA and located no profit in statin-treated, high-risk sufferers.

“The quantity of EPA [was] considerably lower than given in REDUCE-IT,” Armitage mentioned, “but it surely appears to me that in an identical hypertriglyceridemic inhabitants, if the impact have been as a result of EPA, you’d have seen some affect in STRENGTH — and none was seen.”

“The opposite piece of proof is in a paper by Paul Ridker, MD, et al on the adjustments in biomarkers throughout REDUCE-IT,” she mentioned. “A number of inflammatory biomarkers related to atherosclerosis rose throughout the research amongst these allotted mineral oil, however remained largely unchanged within the EPA group. That is in distinction to what’s seen with these biomarkers in different massive trials, the place no adjustments have been seen within the placebo teams, and as soon as once more raises the chance that the obvious advantages of EPA could also be associated to hazard from the mineral oil.”

Nonetheless Room for Profit?

Primarily based largely on the outcomes of REDUCE-IT, Vascepa is at the moment accredited by the US Meals and Drug Administration as an adjunctive remedy to decrease the chance for CV occasions amongst adults with elevated triglyceride ranges (≥150 mg/dL). Sufferers should even have both established CVD or diabetes and two or extra further CV danger components and are suggested to proceed bodily exercise and keep a nutritious diet.

Dr Steven Nissen

Nissen, the principal writer of the STRENGTH trial, advised theheart.org | Medscape Cardiology, “REDUCE-IT is an outlier. Different trials of omega-3 fatty acids, a few of them very massive, confirmed no advantages, and a meta-analysis of practically 78,000 sufferers confirmed no helpful results. On this context,” he mentioned, “the big ‘profit’ noticed in REDUCE-IT does not make any sense.”

Nissen famous {that a} secondary evaluation of STRENGTH additional confirmed that greater plasma EPA ranges didn’t scale back CV outcomes. He additionally highlighted the elevated danger of atrial fibrillation with EPA. “We have to see one other research evaluating EPA to a impartial comparator reminiscent of corn oil, which had no vital impact on lipid or inflammatory biomarkers in STRENGTH,” he mentioned. “With out such a trial, the outcomes of REDUCE-IT can’t be accepted as definitive.”

Ridker, the lead writer of the REDUCE-IT substudy that discovered biomarker adjustments with the mineral oil placebo, advised theheart.org | Medscape Cardiology, “Is it doable that EPA is an excellent drug? Completely, and I proceed to assume it helpful for our very high-risk, secondary-prevention sufferers after we are working out of choices.”

Dr Paul Ridker

“However,” mentioned Ridker, who’s a professor at Harvard Medical College and director of the Heart for Cardiovascular Illness Prevention at Brigham and Girls’s, “the fact…is that ongoing uncertainties want decision.” Like Nissen, he thinks the easiest way to resolve these uncertainties is thru a second trial utilizing a completely impartial comparator. “I’m hopeful that the US Nationwide Institutes of Well being will see match to undertake such an endeavor, maybe with help from trade companions.”

Though Armitage is not in scientific follow, when requested how she may use EPA, she mentioned it may be affordable for sufferers who meet the prescribing standards and stay excessive danger in any case different danger components have been addressed. She added that though EPA is accredited within the UK, she does not assume it’s being broadly prescribed.

Dr Salim Virani

Salim S. Virani, MD, PhD, a professor within the Sections of Cardiology and Cardiovascular Analysis at Baylor Faculty of Drugs who has printed articles about REDUCE-IT and on the eligibility and price of EPA within the US Veterans Affairs system, mentioned in an interview, “In my private opinion, clinicians [should] first optimize weight loss plan and way of life and work on secondary causes, as they play a really huge position in hypertriglyceridemia.” He additionally really helpful optimizing LDL-C ranges due to “constant knowledge displaying that LDL-C management results in vital discount in atherosclerotic CVD occasions.”

“As soon as these two steps are taken and triglycerides nonetheless stay elevated,” he mentioned, “then including EPA in sufferers with established atherosclerotic CVD or these with diabetes plus different CV danger components could also be an inexpensive choice to additional decrease residual atherosclerotic CVD danger.”

Medical Inertia?

Bhatt acknowledged that regardless of the advantage of EPA within the context of REDUCE-IT, “a couple of points stand in the way in which of prescribing, notably within the US.”

Vascepa’s producer Amarin misplaced a patent problem within the US, enabling the comparatively early introduction of a number of generics. “They’ve misplaced curiosity within the US as a result of there are three generics.”

“The unhappy reality is, if there is not a drug rep saying, ‘Hey, have a look at this new knowledge,’ there’s scientific inertia,” mentioned Bhatt. He believes that the dearth of promoting will damage consciousness amongst physicians and “in the end damage sufferers as a result of they will not get the drug.”

Value can be a difficulty, Bhatt affirmed. Vascepa has vital out-of-pocket prices for a lot of sufferers, as do a few of the generics. At the moment, the branded product prices about $300 monthly with out insurance coverage, in accordance with medication.com; costs for generics differ broadly, working wherever from $82 to $200 or extra.

Regardless of these challenges, he famous that many tips world wide have already modified to replicate the info, together with the American Diabetes Affiliation and the US Nationwide Lipid Affiliation.

Will there be one other trial of EPA with a impartial placebo? Bhatt believes it isn’t going to occur. “The corporate that funded REDUCE-IT is struggling simply to remain alive, and one other investigator-funded trial like RESPECT EPA would in all probability be underpowered and never transfer the needle a lot.”

Virani agreed that whereas it will be finest to check EPA towards a completely inert placebo, “whether or not there’s sufficient urge for food to fund such a big trial stays an enormous query.”

In the meantime, Bhatt mentioned, “EPA is just not for everyone, however for the high-risk sufferers who meet the stringent inclusion standards of REDUCE-IT, I believe clinicians ought to at the least contemplate use of EPA in a approach in keeping with the US FDA label, the Canadian label, and the label in elements of Europe the place the drug is being launched.”

Comply with Marilynn Larkin on Twitter:  @MarilynnL

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