A brand new Japanese research of extremely purified eicosapentaenoic acid (EPA; icosapent ethyl) has steered a potential profit in lowering hostile cardiovascular occasions in sufferers with persistent 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 demise, 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 College 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 controversy 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 could have had an hostile impact.
Commenting on the brand new RESPECT-EPA trial for theheart.org | Medscape Cardiology, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, stated the outcomes have been in line with 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 info from this trial and from the sector extra broadly, this collectively reveals a convincing cardiovascular profit with EPA,” Bhatt stated. “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 consider it needs to be used to assist the EPA knowledge from REDUCE-IT.
“The numerous limitations of the RESPECT-EPA trial make it uninterpretable. It simply does not meet modern requirements for medical trials,” Nissen informed theheart.org | Medscape Cardiology. “I do not suppose it sheds any mild in any respect on the controversy 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 distinct excessive dose omega-3 fatty acid product together with a mix 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.
Lately, optimum medical remedy, notably with high-intensity statins, has develop into the gold commonplace of take care of sufferers with coronary artery illness, however they’re nonetheless at considerably excessive residual threat, he famous.
Regardless of of the proof offered by JELIS, the conflicting ends in current omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy concerning the relevance of EPA intervention on high of the most recent optimum medical remedy, Daida stated.
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 persistent 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 extra 4 years from the tip 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 demise, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization, confirmed a borderline vital discount within the EPA group at 6 years for the reason that begin of randomization (10.9% vs 14.9%; hazard ratio [HR], 0.785; P = .0547).
The secondary endpoint, a composite of sudden cardiac demise, MI, unstable angina, and coronary revascularization, confirmed a big discount within the EPA group (8.0% vs 11.3%; HR, 0.734; P = .0306).
By way of hostile 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 put up 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 price (suggesting that the research could also be underpowered), an open-label design, and the truth that baseline ranges of EPA on this Japanese inhabitants could be increased than these in Western international locations.
“Huge Loss” of Sufferers
Critiquing the research, Nissen highlighted the big dropout and protocol violation price.
“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 era many sufferers had dropped out. It might have been a really selective inhabitants that lasted 6 years within the research. Sufferers that drop out are totally different to those 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 point is the open-label design. Everybody knew who’s getting what. Blinding is essential in a research. And there was no management therapy on this trial,” he famous.
The researchers additionally chosen sufferers with low EPA ranges at baseline, Nissen added. “That’s fully totally 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 put up hoc subgroup evaluation displaying a big profit, Nissen stated, “They in contrast a subgroup within the lively therapy arm who had giant will increase in EPA to a subgroup of management sufferers who had the smallest improve in EPA. That might be like evaluating sufferers who had the biggest 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.”
However Bhatt argues that the RESPECT-EPA trial helps the 2 earlier trials displaying advantages of EPA.
“Some could quibble with the P worth, however to me this research has proven clear outcomes, with apparent separation of the Kaplan-Meier curves,” he stated.
“It’s an investigator-initiated research, which is nice in precept however has a number of the ordinary caveats of such a research in that — in all probability as a consequence of funds 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 individuals who have been involved about it,” Bhatt famous.
He identified that the 1800-mg dose of EPA is similar dose used within the JELIS trial and is the dose utilized in Japan. The REDUCE-IT trial used the next dose (4 g), however generally, Japanese folks have increased 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 increased than common American ranges,” he added.
Magnitude of Profit Unsure?
Discussant of the research on the Late Breaking Scientific Trials session, Pam R. Taub, MD, professor of drugs on the College of California San Diego College of Medication, stated, “Regardless of being underpowered with a pattern dimension of 2460, RESPECT-EPA reveals profit in reducing composite coronary occasions.”
“There may be profit with EPA, however the magnitude of profit is unsure,” she said.
Taub identified that there’s a sign throughout research for new-onset atrial fibrillation, however the absolute improve is “fairly small.”
She famous that extra mechanistic and medical knowledge are wanted to hone in on which sufferers will derive probably the most profit, equivalent to these with elevated high-sensitivity C-reactive protein or highest change in EPA ranges. However she concluded that in medical observe, physicians may think about 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
experiences 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. Offered November 6, 2022.
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