A brand new Japanese research of extremely purified eicosapentaenoic acid (EPA; icosapent ethyl) has prompt a potential profit in lowering antagonistic cardiovascular occasions in sufferers with continual coronary artery illness taking statins.
The open-label randomized RESPECT-EPA research confirmed a discount of borderline statistical significance in its major endpoint of a composite of cardiovascular dying, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, unstable angina, and coronary revascularization in sufferers allotted to the EPA product at a dosage of 1800 mg/day.
The outcomes have been offered on the American Coronary heart Affiliation (AHA) Scientific Periods 2022 by Hiroyuki Daida, MD, Juntendo College Graduate Faculty of Medication, Japan.
Nonetheless, the trial has a number of limitations, together with a excessive variety of affected person withdrawals or protocol deviations, and as such its conclusions are unsure.
Regardless, it has inevitably added to the talk on the cardiovascular advantages of EPA, which have been proven within the REDUCE-IT trial. Nonetheless, that trial has been dogged with controversy due to considerations that the mineral oil placebo used might have had an antagonistic impact.
Commenting on the brand new RESPECT-EPA trial for theheart.org | Medscape Cardiology, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, mentioned the outcomes have been per REDUCE-IT and one other earlier Japanese trial, the Japan EPA Lipid Intervention Research (JELIS), and added to the proof supporting cardiovascular advantages of EPA.
“In isolation, this research will not be considered as displaying conclusive advantages; however trying on the totality of the information from this trial and from the sector extra extensively, this collectively reveals a convincing cardiovascular profit with EPA,” Bhatt mentioned. “We now have 3 randomized managed trials all displaying advantages of extremely purified EPA in lowering cardiovascular occasions.”
Nonetheless, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was in no way impressed with the RESPECT-EPA trial and doesn’t imagine it needs to be used to assist the EPA information from REDUCE-IT.
“The various limitations of the RESPECT-EPA trial make it uninterpretable. It simply does not meet up to date requirements for scientific trials,” Nissen advised theheart.org | Medscape Cardiology. “I do not assume it sheds any gentle in any respect on the talk over the efficacy of EPA in heart problems.”
Nissen was the lead investigator of one other largescale trial, STRENGTH, which confirmed no good thing about a special excessive dose omega-3 fatty acid product together with a mixture of EPA and docosahexaenoic acid (DHA).
In his AHA presentation on the RESPECT-EPA research, Daida defined as background that in 2005, JELIS first demonstrated a useful impact of extremely purified EPA on cardiovascular outcomes in sufferers with and with out coronary artery illness.
Just lately, optimum medical remedy, significantly with high-intensity statins, has change into the gold commonplace of look after sufferers with coronary artery illness, however they’re nonetheless at considerably excessive residual threat, he famous.
Regardless of of the proof supplied by JELIS, the conflicting leads to latest omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy concerning the relevance of EPA intervention on prime of the newest optimum medical remedy, Daida mentioned.
The present research — Randomized trial for Evaluating the Secondary Prevention Efficacy of Mixture Remedy Statin and EPA (RESPECT-EPA) — was performed to find out the impact of extremely purified EPA on cardiovascular occasions in Japanese sufferers with continual coronary artery illness and a low EPA/arachidonic acid (AA) ratio (<0.4), who have been already receiving statins.
They have been randomly assigned to extremely purified EPA (icosapent ethyl, 1800 mg/day) plus statin remedy or to statin remedy alone.
The enrollment interval began in 2013 and continued for 4 years. Sufferers have been adopted for an additional 4 years from the top of the enrollment interval.
The trial included 2506 sufferers, 1249 assigned to the EPA group and 1257 to the management group. In each teams there have been a excessive variety of early withdrawals or protocol deviations (647 within the EPA group and 350 within the management group).
The evaluation was performed on 1225 sufferers within the EPA group and 1235 sufferers within the management group, though at 6 years’ follow-up there have been fewer than 400 sufferers in every arm.
Baseline traits confirmed median low-density lipoprotein (LDL) ldl cholesterol ranges of 80 mg/dL, EPA ranges of 45 µg/mL, and triglyceride ranges of 120 mg/dL.
The first endpoint, a composite of cardiovascular dying, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization, confirmed a borderline vital discount within the EPA group at 6 years because the begin of randomization (10.9% vs 14.9%; hazard ratio [HR], 0.785; P = .0547).
The secondary endpoint, a composite of sudden cardiac dying, MI, unstable angina, and coronary revascularization, confirmed a big discount within the EPA group (8.0% vs 11.3%; HR, 0.734; P = .0306).
When it comes to antagonistic occasions, there was a rise in gastrointestinal issues (3.4% vs 1.2%) and new-onset atrial fibrillation (3.1% vs 1.6%) within the EPA group.
In a publish hoc evaluation, which excluded sufferers with a rise of greater than 30 µg/mL within the management group (182 sufferers) and people with a rise of lower than 30 µg/mL within the EPA group (259 sufferers), the first endpoint confirmed a big discount the EPA group (HR, 0.725; P = .0202).
Daida famous that limitations of the research included a decrease than anticipated occasion charge (suggesting that the research could also be underpowered), an open-label design, and the truth that baseline ranges of EPA on this Japanese inhabitants can be greater than these in Western nations.
“Large Loss” of Sufferers
Critiquing the research, Nissen highlighted the massive dropout and protocol violation charge.
“There was an enormous lack of sufferers over the 6- to 8-year follow-up, and the Kaplan- Meier curves did not begin to diverge till after 4 years, by which period many sufferers had dropped out. It could have been a really selective inhabitants that lasted 6 years within the research. Sufferers that drop out are completely different to people who keep in, so they’re cherry-picking the sufferers that persist within the trial. There may be monumental bias right here,” he commented.
“One other weak spot is the open-label design. Everybody knew who’s getting what. Blinding is vital in a research. And there was no management remedy on this trial,” he famous.
The researchers additionally chosen sufferers with low EPA ranges at baseline, Nissen added. “That’s fully completely different speculation to what was examined within the REDUCE-IT and STRENGTH trials. And even with all these issues, the outcomes are nonetheless statistically insignificant.”
On the publish hoc subgroup evaluation displaying a big profit, Nissen mentioned, “They in contrast a subgroup within the energetic remedy arm who had massive will increase in EPA to a subgroup of management sufferers who had the smallest enhance in EPA. That may be like evaluating sufferers who had the most important reductions in LDL in a statin trial to these within the management arm who had no reductions or will increase in LDL. That is scientifically completely inappropriate.”
Supportive Knowledge
However Bhatt argues that the RESPECT-EPA trial helps the 2 earlier trials displaying advantages of EPA.
“Some might quibble with the P worth, however to me this research has proven clear outcomes, with apparent separation of the Kaplan-Meier curves,” he mentioned.
“It’s an investigator-initiated research, which is nice in precept however has a number of the traditional caveats of such a research in that — in all probability as a consequence of price range constraints — it has an open-label design and is underpowered. However as they didn’t use a placebo and nonetheless confirmed a good thing about EPA, that helps resolve the difficulty of the placebo utilized in REDUCE-IT for many who have been involved about it,” Bhatt famous.
He identified that the 1800-mg dose of EPA is identical dose used within the JELIS trial and is the dose utilized in Japan. The REDUCE-IT trial used the next dose (4 g), however typically, Japanese individuals have greater ranges of EPA than Western populations, he defined.
“Whereas this trial included sufferers with decrease ranges of EPA, what is taken into account low in Japan is far greater than common American ranges,” he added.
Magnitude of Profit Unsure?
Discussant of the research on the Late Breaking Medical Trials session, Pam R. Taub, MD, professor of drugs on the College of California San Diego Faculty of Medication, mentioned, “Regardless of being underpowered with a pattern measurement of 2460, RESPECT-EPA reveals profit in lowering composite coronary occasions.”
“There may be profit with EPA, however the magnitude of profit is unsure,” she acknowledged.
Taub identified that there’s a sign throughout research for new-onset atrial fibrillation, however the absolute enhance is “relatively small.”
She famous that extra mechanistic and scientific information are wanted to hone in on which sufferers will derive essentially the most profit, comparable to these with elevated high-sensitivity C-reactive protein or highest change in EPA ranges. However she concluded that in scientific apply, physicians might contemplate addition of EPA for discount of residual threat in secondary prevention sufferers.
The RESPECT-EPA research was supported by the Japan Coronary heart Basis. Daida
reviews s peakers’ bureau/honorarium charges from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Firm, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura & Co and TOA EIYO, and analysis funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.
American Coronary heart Affiliation (AHA) 2022 Scientific Periods. Presentation 19455. Introduced November 6, 2022.
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