Questions about the cardiovascular benefits shown in the REDUCE-IT study with icosapentethyl, a high-dose eicosapentaenoic acid (EPA) product, were rekindled with a new analysis from the STRENGTH study that found no benefit from a high-dose combined omega 3-Fatty Acids shows fatty acid product in patients who achieved the highest EPA values and who suffered no harm in those with the highest docosahexaenoic acid (DHA) values.
STRENGTH researcher Steven Nissen, MD said these new results heightened concern about the positive outcome of the previously reported REDUCE-IT study and suggest that “there is no strong evidence of any benefit from fish oil in preventing major cardiovascular events gives.”
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 an increase 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 science session on May 16, while it was also published on JAMA Cardiology.
The REDUCE-IT study showed a significant 25 reduction in the relative risk of cardiovascular events in patients taking icosapentethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, 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 of REDUCE-IT came about and why they weren’t replicated in the STRENGTH study.
Nissen noted that several hypotheses were proposed. This includes a potential side effect of the mineral oil placebo in the REDUCE-IT study, which may have an increased risk in the placebo treatment group and which led to a false positive result for icosapentethyl. Another possibility is that the moderately higher plasma levels of EPA 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.
STÄRKE’s current post-hoc analysis was carried out to examine these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and the levels of EPA, DHA achieved or changes in the levels of 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 there was no benefit from achieving high EPA levels or no harm from achieving high DHA levels, which, according to the authors, “adds to concerns that the choice of comparator was observed in the two divergent results could have influenced attempts. “
“Unlike corn oil, which is inert, mineral oil has powerful side 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 ingredient can mistakenly look really good. ”
In the STRENGTH study, 13,078 people at high risk for major cardiovascular events were randomized to receive 4 g of the EPA / DHA combination product (omega-3 carboxylic acid) or corn oil as placebo. The main results reported previously showed no difference between the two groups in terms of the primary endpoint – a combination of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina that required hospitalization.
The current analysis of 10,382 patients with available omega-3 fatty acid levels examined the event rates by tertile of the achieved EPA and DHA levels. The median EPA plasma level in patients taking the omega-3 product was 89 µg / ml, with the top tertile reaching 151 µg / ml (an increase of 443%). Nissen indicated that this was higher than the median EPA reported in the REDUCE-IT study (144 µg / ml).
The median DHA level was 91 µg / ml and increased in the STRENGTH analysis to 118 g / ml (a 68% increase) in the uppermost tertile.
The results showed no difference in the occurrence of the previously specified primary endpoint in patients treated with omega-3 carboxylic acid who were in the upper tertile of the EPA values achieved after 1 year (event rate 11.3%) compared with patients treated with corn oil were treated (11.0.). %), a non-significant difference (hazard ratio 0.98; P = 0.81).
For DHA, patients in the top 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 examined 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 connection with the increased risk of atrial fibrillation in omega-3 studies, they raise uncertainty as to whether an omega-3 supplement has a net benefit or a net harm,” concluded Nissen.
He suggested that the choice of placebo comparison could play an important role in determining the outcome of studies using omega-3 products, adding that more research is needed with studies specifically comparing corn oil to mineral oil and to compare purified EPA with other formulations of Omega. 3 fatty acids were developed.
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 said.
REDUCE-IT investigator answers
Speaking to the STRENGTH analysis that followed at the ACC presentation, Deepak L. Bhatt, MD, who was the lead investigator of the REDUCE-IT study, suggested that one conclusion might be that “the lack of a relationship in a negative study says nothing “. so much more than that particular drug not working. “
Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, told theheart.org | Medscape Cardiology that comparisons should not be made between studies with different products.
“I commend the STRENGTH researchers for a well-conducted study that provided a definitive answer to the specific drug they were studying and found no benefit. But in a completely negative study, I wouldn’t necessarily expect a link between a biomarker and the result, “he said.
“Regarding icosapentethyl (pure EPA) every cardiovascular study has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo) and a few 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 specifically achieved with icosapentethyl 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 biomarkers -To focus on changes.
“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 in EPA was via a completely different drug with many different properties, “he added.
In his discussion of the study at the ACC presentation, Bhatt pointed out that there was no overall reduction in serious adverse cardiovascular events in the STRENGTH study despite a 19% reduction in triglycerides, which in his opinion was a “very interesting interruption ” be. 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 an almost identical amount, 19%, but we don’t see any association 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 the patients with higher EPA levels on the STRENGTH analysis, but Nissen countered, “I don’t think this was enough of a difference to explain the lack of an effect . “
Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, 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 done as a direct study of the two omega-3 products or the two different placebo oils.
The STRENGTH study was sponsored by Astra Zeneca. Nissen reports 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 supervisory body for data security with Contego; other positions at TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, 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, Afimmune, 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, Ironwood, Ischemix, Lexicon, 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 on May 16, 2021.
JAMA Cardiol. Published online May 16, 2021. Full text
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