Questions about the cardiovascular benefits shown in the REDUCE-IT test with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, has been reactivated with a new STRENGTH assay analysis that shows no benefit from a combined high-dose omega-3 fatty acid in patients who have reached the highest EPA levels and have not caused harm. in those with the highest levels of docosahexaenoic acid (DHA).
FORCE researcher Steven Nissen, MD, said these new findings add to concerns about the positive outcome in previous reports REDUCE IT and suggest that “there is no clear evidence of a benefit of fish oil in the prevention of major cardiovascular events “.
But Nissen, who chairs the Department of Cardiovascular Medicine at the Cleveland Clinic in Ohio, noted evidence of damage, with the reduction in atrial fibrillation with high-dose omega-3 fatty acid products.
“Fish oils substantially increase the risk of atrial fibrillation and there is no solid evidence to help the heart in any way,” he stated.
The new FORCE analysis was presented on May 16 at the American College of Cardiology (ACC) 2021 virtual science session and was presented published simultaneously inside Cardiology JAMA.
The REDUCE-IT trial showed a significant reduction in the relative risk of 25% in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared to patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the EPA / DHA mixed product (Epanova, AstraZeneca), compared to a placebo corn oil.
The different results of these two studies have led to many questions about how the benefits seen in REDUCE-IT were obtained and why they were not replicated in the STRENGTH study.
Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of placebo mineral oil in the REDUCE-IT trial, which may have a high risk in the placebo treatment group and lead to a false-positive result for ethyl icosapent. Another possibility is that moderately higher plasma EPA levels achieved in REDUCE-IT were responsible for the observed benefits or that co-administration of DHA to STRENGTH could counteract the potential beneficial effects of EPA.
The current post hoc analysis of STRENGTH was carried out to address these last two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in the levels of these fatty acids.
“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Nissen said.
The results of the new analysis showed the absence of a benefit in achieving high levels of EPA or harm in achieving high levels of DHA which, according to the authors, “reinforces the concern that the choice of comparator may have influenced the divergent results observed in the two trials “.
“Unlike corn oil, which is inert, mineral oil has greater adverse effects, increasing LDL [low-density lipoprotein] 10.9% and CRP [C-reactive protein] 32% in the REDUCE-IT trial, “Nissen said.” If you take a toxic placebo, the active drug may look bad. ”
The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of combined product EPA / DHA (omega-3 carboxylic acid) or corn oil as placebo. Main results, previously reported, showed no difference between the two groups in terms of the primary outcome: a cardiovascular death compound, myocardial infarction, stroke, coronary revascularization or unstable angina which requires hospitalization.
The current analysis, in 10,382 patients with available levels of omega-3 fatty acids, examined event indices according to one-third of the levels achieved by EPA and DHA. The mean plasma EPA level for patients taking the omega-3 product was 89 µg / mL, with the upper third reaching levels of 151 µg / mL (an increase of 443%). Nissen noted that it was above the mean EPA level reported in the REDUCE-IT assay (144 µg / mL).
The mean DHA level was 91 µg / mL, rising to 118 g / mL (a 68% increase) in the upper third of the FORCE analysis.
The results showed no difference in the appearance of the pre-specified primary outcome among patients treated with omega-3 carboxylic acid who were in the upper third of EPA levels achieved at 1 year (event rate, 11, 3%) compared with patients treated with corn oil (11.0%), a non-significant difference (risk ratio, 0.98; Pg = .81).
Regarding DHA, patients in the upper third of the achieved DHA levels had an event rate of 11.4%, compared to 11.0% in the corn oil group. , also a non – significant difference (risk ratio, 1.02; Pg = .85)
Sensitivity analyzes based on the highest third of changes in EPA or DHA levels showed similar neutral results.
Because plasma levels may not reflect tissue EPA or DHA levels, additional analyzes assessed red blood cell EPA and DHA levels, none of which showed evidence of benefits or harms.
“These results suggest that omega-3 fatty acid supplementation in high-risk cardiovascular patients is neutral even at the highest levels achieved,” Nissen said. “And, in the context of an increased risk of atrial fibrillation in omega-3 trials, they generate uncertainty about whether there are net benefits or harms with any omega-3 preparation,” Nissen concluded.
He suggested that the choice of placebo comparator could play an important role in determining the outcome of omega-3 product trials, adding that further research is needed with trials specifically designed to compare wheat oil. corn with mineral oil and compare purified EPA with other omega -3 fatty acid formulations.
At an ACC press conference, Nissen said it could not recommend the use of omega-3 fatty acid products cardiovascular risk reduction given the uncertainty about the benefit of REDUCE-IT.
“We need replication and the problem is that STRENGTH did not replicate REDUCE-IT,” he stated.
REDUCE-IT The researcher answers
Discussing the FORCE analysis after the ACC filing, Deepak L. Bhatt, MD, principal investigator of the REDUCE-IT trial, suggested that one conclusion might be that “the absence of relationship in a negative judgment does not explains it works much better for us than this specific drug. “
Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, said theheart.org | Cardiology Medscape that no comparisons should be made between different trials with different products.
“I congratulate STRENGTH researchers for a well-conducted trial that provided a definitive answer on the specific drug they studied, without finding any benefit. But in a completely negative trial, I would not necessarily expect to see a relationship between any biomarker and the result, “he said.
With respect to ethyl icosapent (pure EPA), so far all cardiovascular trials have been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORAT (randomized, placebo-controlled), CHERRY randomized, no placebo) and some smaller ones, ”Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher levels of EPA achieved specifically with icosapent ethyl are beneficial.”
Noting that all glucagon-like peptide-1 agonists reduce glucose, for example, but not all reduce cardiovascular events, Bhatt said it was best to focus on the results of clinical trials and not focus excessively on the results of clinical trials. biomarker changes.
“Yes, the STRENGTH drug increased the EPA (and increased the DHA, in addition to lowering the triglycerides), but the REDUCE-IT and JELIS drug increased the EPA much more, without increasing the DHA, and more importantly, the increase in EPA was through a completely different drug, with many different properties, ”he added.
In his discussion of the study at the ACC presentation, Bhatt noted that in the STRENGTH trial there was generally no reduction in major adverse cardiovascular events despite a 19% reduction. triglycerides, who said it was a “very interesting disconnect”. In this analysis, he asked Nissen what was the reason for observing no relationship between EPA or DHA level and triglyceride reduction.
Nissen said it was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship to that and the EPA levels achieved.” He suggested that this may be due to different threshold levels.
Bhatt also noted that the use of high-intensity statin was lower in patients with higher EPA levels in the FORCE analysis, but Nissen countered: “I don’t think the difference was enough to explain the lack of an effect “.
Guest commentator on the new analysis at an ACC press conference, Dr. Eileen Handberg, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCTION trials. “These new findings are important because they potentially explain why these results are different,” he said.
Handberg, who is a professor of medicine at the University of Florida in Gainesville, said he hopes the additional research requested by Nissen will continue as a direct study of the two omega-3 products or the two different placebo oils.
The STRENGTH trial 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; data security control board activities with Contego; other roles with 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.
Scientific Session of the American College of Cardiology (ACC) 2021. Presented May 16, 2021.
JAMA Cardiol. Published online May 16, 2021. Full text