Rx Omega-3 No Better Than Corn Oil for Preventing CV Events

Astra-Zeneca’s Epanova—a highly processed carboxylic acid form of EPA and DHA– failed to deliver the expected reduction in major cardiovascular events observed during 2019’s REDUCE-IT trial using the fish oil-based Vascepa EPA.

The just-published multicenter STRENGTH trial  ( (STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) randomized 13,078 high-risk patients to treatment with either 4 grams per day of Epanova, called “omega-3 CA” in the study, or a corn oil placebo, which the researchers arguably considered “inert.

All patients had some combination of established cardiovascular disease, diabetes, overweight, hypertriglyceridemia or low HDL levels. The study interventions were added on top of the patients’ existing drug regimens. The majority was on statins.

The primary outcomes assessed were major adverse cardiovascular events (MACE) including CVD-related death, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, or admissions for coronary revascularization procedures.

An Early End

The STRENGTH researchers, based at 675 centers in 22 different countries worldwide, began the study in 2014, and intended to carry on the evaluation until a total of 1,600 patients had had one or more of the index cardiovascular events. But they opted to end the trial earlier this year, after 1,384 patients had index events.

At that point an interim analysis showed absolutely no difference between Epanova and the corn oil placebo in terms of reducing MI, stroke, or unstable angina (Nicholls SJ, et al. JAMA. 2020).

Of the 6,539 patients treated with omega-3 CA, 785 patients (12.0%) had major events. Among the 6,539 on the corn oil placebo, there were 795 events (12.2%).

The investigators decided that after 6 years of follow up, any potential benefit from the drug would have become apparent, so it was unlikely that continuing the study would change the ultimate conclusion.

The findings are surprising for three reasons.

Astra-Zeneca was betting big on its omega-3 carboxylic acid drug, Epanova, as a means of capturing a piece of the multi-billion dollar prescription omega-3 market

First, the omega-3 CA did reduce triglyceride, non-HDL cholesterol, and hs-CRP levels compared with the corn oil placebo. Based on this, it is entirely reasonable to expect that these changes would lead to a reduction in MACE.

Second, there was a small but significant increase in new-onset atrial fibrillation in the Epanova cohort compared with those on placebo (2.2% versus 1.3%), suggesting that in some people, addition of an omega-3 drug might actually raise rather than lower overall cardiovascular risk.

An interim analysis showed absolutely no difference between Epanova and the corn oil placebo in terms of reducing MI, stroke, or unstable angina

Third, the STRENGTH findings diverge from the more promising REDUCE-IT study (Reduction of Cardiovascular Events With EPA – Intervention Trial), which showed that among 8,179 high risk patients, 2 g of Vascepa twice daily (on top of whatever other drugs they were taking) a very significant 25% reduction in the risk of ischemic events, including cardiovascular death (Bhatt DL, et al. N Engl J Med. 2019).

REDUCE-IT and STRENGTH are very similar in trial designs, patient populations, and study endpoints. The main differences were the particular omega-3 drug being tested, and the type of placebo used for comparison; STRENGTH used corn oil, REDUCE-IT used mineral oil.

Unanswered Questions

The reasons for the unexpected lackluster performance of omega-3 CA are not entirely clear, but there are several possible explanations. One is that the patients had already reached optimum risk reduction via statins, other drugs, and whatever diet/lifestyle changes they’d already made that any additional benefit from the omega-3 drug would be negligible.

This is plausible, but it does not explain the difference between STRENGTH and REDUCE it.

Though there’s never been a head-to-head comparison of Epanova versus Vascepa for secondary prevention of MACE, it may simply be that the latter confers certain benefits that the former does not.  Some have suggested that the DHA present in Epanova might be detrimental because it can potentially raise LDL cholesterol.

The STRENGTH trial is a major disappointment for Astra-Zeneca, and it raises the question of whether Epanova has any meaningful role to play in secondary prevention of cardiovascular disease.

There’s also a question of whether either placebo—corn oil or mineral oil—is truly inert from a cardiometabolic viewpoint. Many in the holistic/functional medicine world would argue that corn oil is bioactive and certainly not inert.

In summary, the STRENGTH trial is a major disappointment for Astra-Zeneca, and it raises the question of whether Epanova has any meaningful role to play in secondary prevention of cardiovascular disease.

The company was betting big on the drug as a way to capture a chunk of the multi-billion dollar prescription omega-3 market.  

It is not clear whether these findings have any relevance for the use of omega-3 supplements—or consumption of omega-3 rich foods—as part of a heart-healthy diet. But they do underscore the challenges inherent whenever pharmaceutical companies purify and concentrate a nutrient with the intention of marketing it as a targeted disease therapy.

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