Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).
STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”
Dr Steven Nissen
But Nissen, who is chair of the Department of Cardiovascular Medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.
“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.
The new STRENGTH analysis was presented May 16 at the virtual American College of Cardiology (ACC) 2021 Scientific Session and was simultaneously published in JAMA Cardiology.
The REDUCE-IT trial showed a large 25% relative risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.
The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.
Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.
The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in 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.
Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns 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 major adverse effects, increasing LDL [low-density lipoprotein] by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”
The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome — a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.
The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 µg/mL, with the top tertile achieving levels of 151 µg/mL (a 443% increase). Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 µg/mL).
The median level of DHA was 91 µg/mL, rising to 118 g/mL (a 68% increase) in the top tertile in the STRENGTH analysis.
Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%) compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).
For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4%, vs 11.0% in the corn oil group, also a nonsignificant difference (hazard ratio, 1.02; P = .85)
Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.
Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.
“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” Nissen concluded.
He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.
At an ACC press conference, Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.
“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.
REDUCE-IT Investigator Responds
Discussant of the STRENGTH analysis following at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”
Dr Deepak L. Bhatt
Bhatt, who is 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 different trials using different products.
“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.
“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (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 EPA levels attained specifically with icosapent ethyl are beneficial.”
Pointing out that all the glucagon-like peptide-1 agonists lower glucose, for example, but not all reduce cardiovascular events, Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.
“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA — and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.
In his discussion of the study at the ACC presentation, Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction.
Nissen said that 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 with that and EPA levels achieved.” He suggested this may be because of different threshold levels.
Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Nissen countered: “I don’t think that 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 behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.
Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.
The STRENGTH trial 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/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring 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.
American College of Cardiology (ACC) 2021 Scientific Session. Presented May 16, 2021.
JAMA Cardiol. Published online May 16, 2021. Full text
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