Questions about the cardiovascular benefits demonstrated in the REDUCE-IT study with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, were re-asked with a new analysis from the STRENGTH study that found no benefit of a high-dose omega combined -3 fat shows fatty acid product in patients with the highest EPA levels and without harm in patients with the highest docosahexaenoic acid (DHA) levels.

Steven Nissen, MD of STRENGTH said these new results increase concern about the positive outcome of the previously reported REDUCE-IT study and suggest that “there is no clear evidence of any benefit from fish oil in preventing major cardiovascular events” .

Dr. Steven Nissen

However, Nissen, chairman of the cardiovascular medicine division at Cleveland Clinic in Ohio, pointed to evidence of damage, with both REDUCE-IT and STRENGTH showing increases in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils significantly increase the risk of atrial fibrillation, and there is no solid evidence that they help the heart in any way,” he said.

The new STRENGTH analysis was presented at the American College of Cardiology (ACC) 2021 virtual scientific session on May 16, while it was also published on JAMA Cardiology.

The REDUCE-IT study showed a large 25% relative risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified EPA formulation, compared to patients taking a mineral oil placebo. However, a similar study, STRENGTH, showed no effect of a similarly high dose of the mixed EPA / DHA product (Epanova, AstraZeneca) compared to a corn oil placebo.

The different results of these two studies have led to many questions about how the benefits achieved in REDUCE-IT were achieved and why they were not repeated in the STRENGTH study.

Nissen noted that several hypotheses were proposed. This includes a possible adverse effect of the mineral oil placebo in the REDUCE-IT study, which has an increased risk in the placebo treatment group and can lead to a false positive result for icosapent ethyl. Another possibility is that the moderately higher EPA plasma levels achieved in REDUCE-IT were responsible for the observed benefits, or that co-administration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

STRENGTH’s current post hoc analysis was carried out to examine these latter two possibilities. The aim was to evaluate the relationship between cardiovascular results and achieved EPA, DHA or changes in these fatty acids.

“In our new analysis, we found no evidence that EPA is beneficial or DHA harmful in patients treated with fish oil,” said Nissen.

The results of the new analysis indicated that achieving high EPA levels was of no benefit or achieving high DHA levels was of no benefit, which the authors believe “increases concerns that the choice of comparator will affect the different results observed in both cases might have attempts. “

“Unlike inert corn oil, mineral oil has significant adverse effects and increases LDL [low-density lipoprotein] by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT study, “said Nissen.” If you give a toxic placebo, the active drug may mistakenly look really good. ”

In the STRENGTH study, 13,078 people at high risk for major cardiovascular events were randomly selected to receive 4 g of the combined EPA / DHA (omega-3 carboxylic acid) product or corn oil as a placebo per day. The main results reported previously showed no difference between the two groups in terms of the primary outcome – a combination of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis of 10,382 patients with available omega-3 fatty acid levels examined the event rates based on the tertiles of the EPA and DHA levels achieved. The mean plasma EPA for patients taking the omega-3 product was 89 µg / ml, with the upper tertile reaching 151 µg / ml (an increase of 443%). Nissen pointed out that this was higher than the mean EPA value given in the REDUCE-IT study (144 µg / ml).

The mean DHA level was 91 µg / ml and increased in the STRENGTH analysis to 118 g / ml (an increase of 68%) in the upper tertile.

The results showed no difference in the occurrence of the specified primary result in patients who were treated with omega-3 carboxylic acid and were in the upper tertile of the EPA values ​​achieved after 1 year (event rate 11.3%), compared to patients who were those treated with corn oil (11.0%), a non-significant difference (hazard ratio, 0.98; P = 0.81).

With DHA, patients in the upper tertile of the DHA values ​​achieved had an event rate of 11.4% compared to 11.0% in the corn oil group, also a non-significant difference (hazard ratio, 1.02; P = 0.85).

Sensitivity analyzes based on the highest tertile change in EPA or DHA levels showed similarly neutral results.

Since the plasma levels may not reflect the EPA or DHA tissue levels, the EPA and DHA levels of the red blood cells were evaluated in additional analyzes, of which there were no indications of benefit or harm.

“These results suggest that omega-3 fatty acid supplementation in high-risk cardiovascular patients is neutral even at the highest levels achieved,” said Nissen. “And in the context of the increased risk of atrial fibrillation in omega-3 studies, they raise uncertainty as to whether an omega-3 supplement has any net benefit or harm,” concluded Nissen.

He suggested that the choice of placebo comparator could play an important role in determining the outcome for trials with omega-3 products, adding that more research is needed with trials specifically designed to use corn oil Compare Mineral Oil and Compare Purified EPA to Other Omega Formulations -3 Fatty Acids.

Speaking at an ACC press conference, Nissen said he could not recommend the use of omega-3 fatty acid products to reduce cardiovascular risk given the uncertainty about the benefits of REDUCE-IT.

“We need replication and the problem is that STRENGTH REDUCE-IT was not replicating,” he explained.

REDUCE-IT Investigator answers

Deepak L. Bhatt, MD, the lead investigator on the REDUCE-IT study, spoke about the STRENGTH analysis that followed the ACC presentation and suggested that one conclusion might be that “the lack of a relationship in a negative study says nothing. ” us so much other than this specific drug doesn’t work. “

Dr. Deepak L. Bhatt

Bhatt, executive director of interventional cardiovascular programs at the Heart & Vascular Center at Brigham and Women’s Hospital in Boston, Massachusetts, told theheart.org | Medscape Cardiology states that comparisons should not be made between different studies on different products.

“I recommend STRENGTH researchers to do a well-conducted study that gave a definitive answer to the drug they were studying and found no benefit. However, in a completely negative study, I wouldn’t necessarily expect a link between a biomarker and the outcome,” he said said.

“Regarding icosapent ethyl (pure EPA), every cardiovascular study has been positive so far: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo) and some smaller ones, “added Bhatt. “Both REDUCE-IT and JELIS found associations between higher EPA levels and lower cardiovascular event rates, suggesting that higher EPA levels achieved specifically with icosapent Ethyl are beneficial.”

Pointing out that all glucagon-like peptide-1 agonists, for example, lower glucose but not all cardiovascular events, Bhatt said it was best to focus on the results of clinical trials and not focus too much on changes focus on the biomarker.

“Yes, the drug in STRENGTH increased EPA (and increased DHA and decreased triglycerides), but the drug in REDUCE-IT and JELIS increased EPA much more without increasing DHA – and more importantly, the increase the EPA was made over a completely different drug with many different properties, “he added.

In his discussion of the study at the ACC presentation, Bhatt pointed out that the STRENGTH study showed no overall reduction in serious adverse cardiovascular events despite a 19% reduction in triglycerides, which he called a “very interesting interruption” designated. He asked Nissen what he thought was the reason for the observation in this analysis that there was no association between EPA or DHA levels and triglyceride reduction.

Nissen said that was an interesting point. “If we look at the two studies, they both reduced triglyceride levels by a nearly identical amount of 19%, but we see no correlation between that and the EPA levels achieved.” He suggested that this could be due to different thresholds.

Bhatt also noted that high-intensity statin use was lower in patients with higher EPA levels in the STRENGTH analysis, but Nissen countered, “I don’t think this was enough difference to explain the lack of an effect.”

Eileen Handberg, PhD, invited the commentator on the new analysis to an ACC press conference and said it was important to try to understand the reasons for the different results of the STRENGTH and REDUCE-IT studies. “These new findings are important because they may explain why these results are different,” she said.

Handberg, a professor of medicine at the University of Florida, Gainesville, said she hoped the additional research Nissen requested would be conducted as a head-to-head study of the two omega-3 products or the two different placebo oils.

The STRENGTH study was sponsored by Astra Zeneca. Nissen reports on research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer and Silence Therapeutics. Bhatt Reports Constant Fees / Fees From CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; Activities of the monitoring committee for data security with Contego; Further functions at TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Klinische Kardiologie, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck & Co., MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications / Cardiology Research Foundation; and research grants from Abbott, Afimmun, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Eisenholz, Ischemix, Lexikon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda and The Medicines Company.

American College of Cardiology (ACC) scientific session 2021. Presented May 16, 2021.

JAMA Cardiol. Published online on May 16, 2021. Full text

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