STRENGTH: No CV benefit with omega-3 carboxylic acid
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Administration of high-dose omega-3 carboxylic acid compared with corn oil placebo did not reduce incidence of major adverse CV events among statin-treated adults with elevated triglycerides at high CV risk.
The findings from the STRENGTH trial, presented at the virtual American Heart Association Scientific Sessions, are in stark contrast to the REDUCE-IT trial, presented in 2018, which demonstrated that icosapent ethyl (Vascepa, Amarin Pharmaceuticals), a pharmaceutical-grade omega-3 fatty acid, was superior to placebo for reducing risk for ischemic events in a similar patient group. As Healio previously reported, the STRENGTH study was stopped early by AstraZeneca in January at the recommendation of the data safety monitoring board due to lack of observed benefit.
“STRENGTH is extraordinarily provocative,” Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, and study chair for the STRENGTH trial, told Healio. “It shows no effect of a high dose of fish oil for patients with high triglycerides and low HDL cholesterol. It really brings into question — into serious question — whether REDUCE-IT is a true positive trial or a false positive trial.”
Study design
For STRENGTH, a double-blind, randomized trial conducted across 675 sites in 22 countries, researchers analyzed data from statin-treated adults with high CV risk, hypertriglyceridemia and low HDL (mean age, 63 years; 35% women; 70% with diabetes; median LDL, 75 mg/dL; median triglycerides, 240 mg/dL; median HDL, 36 mg/dL).
Participants were randomly assigned 4 g daily omega-3 carboxylic acid (Epanova, AstraZeneca; n = 6,539) or corn oil (n = 6,539) on top of the usual background therapies, including statins.
“Corn oil was deliberately chosen, as it has a neutral effect on chemical parameters, whereas mineral oil [used in REDUCE-IT] is a negative control,” A. Michael Lincoff, MD, director of C5 research, vice chairman for research, cardiovascular medicine and professor of medicine at the Cleveland Clinic Coordinating Center for Clinical Research, said during a press conference.
The primary efficacy outcome, a composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina requiring hospitalization, occurred in 12% of patients treated with omega-3 carboxylic acid vs. 12.2% treated with corn oil, for an HR of 0.99 (95% CI, 0.9-1.09; P = .84).
The findings were simultaneously published in JAMA.
Researchers observed a significantly higher incidence of atrial fibrillation among participants in the omega-3 carboxylic acid group compared with placebo (HR = 1.69; 95% CI, 1.29-2.21; nominal P < .001), as well as more gastrointestinal adverse events in the omega-3 carboxylic acid group vs. placebo (24.7% vs. 14.7%).
The biochemical parameters reflected the chemical effect of the drug, Lincoff said. Triglyceride levels were reduced by 19% and high-sensitivity C-reactive protein was reduced by 20% among those who received omega-3 carboxylic acid.
“Despite the biochemical effects, there was no difference in the outcome with treatment of omega-3 carboxylic acid, with superimposable survival curves and an HR of 0.99,” he said.
“These findings, in context of the increased risk for AF and other trials of omega-3 fatty acids, casts a question on whether there is a net benefit or harm with any omega-3 fatty acid preparation,” Lincoff said.
‘Jury is still out’
The REDUCE-IT study, which enrolled 8,179 patients who had fasting triglycerides 135 mg/dL to 499 mg/dL despite taking statins and who had established CVD (70.7%) or diabetes plus other risk factors (29.3%), showed a reduction in CV events that was “quite large” vs. mineral oil placebo, according to Alberico L. Catapano, MD, PhD, full professor of pharmacology at the University of Milano, director of the Laboratory for the study of Lipoproteins and Atherosclerosis and of the Center for the Study of Atherosclerosis of the Italian Society of Atherosclerosis. Participants in REDUCE-IT were assigned icosapent ethyl 2 g twice daily or placebo and followed for a median of 4.9 years; Catapano suggested that the difference in dose between the two studies could have influenced the different findings.
Catapano proposed several other theories to explain the discrepancies between trials. Omega-3 carboxylic acid is a purified blend of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Icosapent ethyl — which is pure EPA — seems to produce higher EPA levels, whereas DHA may be less biologically active. Studies show EPA preserves membrane structure and the normal distribution of cholesterol, inhibits lipid oxidation and influences signal transduction pathways related to inflammation and vasodilation, Catapano said.
“The unfavorable effect of mineral oil placebo has been alluded to. Is there something to this? We do not know,” Catapano said during a discussion after the presentation. “Some data seems to suggest yes; some data seems to suggest no. The jury is still out.”
“What I’m trying to say here today is that what makes the difference is unclear,” Catapano said. “We need to certainly address the points of doses, plasma levels, as well as the effect of placebo. Whether these would explain the differences is still unclear, but, certainly, a comparative trial may be important, bearing in mind the dose effect.”
Reference:
Perspective
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I am not surprised by the results of STRENGTH for a variety of reasons.
Even before AstraZeneca issued a press release that announced this trial would be stopped early due to lack of efficacy, I speculated the findings would be neutral. I have been following the science for a while with respect to omega-3 fatty acids. It is pretty clear that not all omega-3 fatty acids are created equal. At a distance, many people — including some clinical trialists — don’t really understand the science. Anyone who did would realize that pure eicosapentaenoic acid (EPA) is where the action is.
The JELIS trial, published in 2007 in The Lancet (Yokoyama M, et al. Lancet. 2007; doi:10.1016/S0140-6736(07)60527-3.) also studied icosapent ethyl, albeit at a lower dose than used in REDUCE-IT. In that study, researchers saw a 19% relative risk reduction in a primary and secondary prevention population, half of whom had normal triglycerides at baseline. The major critique of that randomized trial was that it was open-label, meaning no placebo. That is a major limitation, but it rebuts concerns about the mineral oil placebo in REDUCE-IT being toxic.
Additionally, a recent nonrandomized but matched comparison of mineral oil placebo with a cellulose-based placebo, published in the basic science journal Cardiovascular Research (Lakshmanan S, et al. Cardiovas Res. 2020; doi:10.1093/cvr/cvz329), showed superimposable rates of plaque progression.
A recent review in Arteriosclerosis, Thrombosis and Vascular Biology that explains the science behind EPA (Mason RP, et al. Arterioscler Thromb Vasc Biol. 2020; doi:10.1161/ATVBAHA.119.313286.) shows DHA may counter some of the benefits of EPA. As well, it may not just be blood EPA levels that matter, but also how the EPA is delivered and how tissue levels are achieved; the formulation tested in STRENGTH may not have been ideal in that regard. Even the first author of STRENGTH has produced such research; a paper on which he was the senior author at the 2020 American College of Cardiology Congress shows the importance of EPA, despite the critical tone taken in the STRENGTH paper.
STRENGTH is a negative trial, as many well-done trials are. There is nothing wrong with that. But it does advance the field by showing that just because a drug lowers triglycerides, it does not mean that it can lower CV events, and that you can’t extrapolate from one trial of one specific drug to another.
Perspective
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Pradeep Natarajan, MD
Given the strong inverse correlation between fatty fish consumption and circulating omega-3 fatty acid concentrations and CVD risk, there has been longstanding interest in using omega-3 fatty acids in pills to reduce CVD risk. Nearly all of the omega-3 fatty acid trials have used lower doses of multiple omega-3 fatty acids. A notable exception is that multiple randomized controlled trials of high-dose EPA alone, or icosapent ethyl, have shown evidence of CVD benefit. These trials are JELIS, REDUCE-IT and EVAPORATE. While STRENGTH also tested a high dose of omega-3 fatty acids, this was a combination EPA and DHA product.
The results of STRENGTH are important and leave us with more questions. A recurring concern has been whether the mineral oil placebo used in icosapent ethyl trials led to increased risk, but it is hard to imagine that this alone is responsible for the relatively large risk reduction observed in REDUCE-IT. We would be more reassured if we fully understood how high-dose EPA may reduce CVD risk, and how this might be distinct from a high-dose EPA and DHA combination. Importantly, the trial populations studied in STRENGTH and REDUCE-IT, high CV-risk individuals with persistent hypertriglyceridemia and adequately lowered LDL, are at very high risk for CVD events. I am enthusiastic about ongoing efforts to understand how to best mitigate risk in this subgroup.
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Lincoff AM. LBS.04: Fish oil, fancy drugs and frustrations in lipid management. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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