CHICAGO — A proprietary fish oil cut the risk of ischemic events among patients taking the formulation for primary or secondary cardiovascular disease (CV) prevention in the REDUCE-IT trial.
For the study’s primary endpoint, icosapent ethyl (Vascepa) significantly reduced major adverse CV events — combined CV death, non-fatal MI, non-fatal stroke, coronary revascularization, and unstable angina — over a median of 4.9 years (17.2% vs 22.0% with placebo, HR 0.75, 95% CI 0.68-0.83).
Similarly, the key secondary endpoint of CV death, non-fatal MI, and non-fatal stroke also yielded an advantage with icosapent ethyl (11.2% vs 14.8%, HR 0.74, 95% CI 0.65-0.83).
And CV death alone was reduced by 20% (4.3% vs 5.2%, HR 0.80, 95% CI 0.66-0.98), Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital in Boston, reported.
REDUCE-IT was presented here at the American Heart Association’s annual meeting and published simultaneously online in the New England Journal of Medicine.
The results are “truly extraordinary” given the magnitude of CV event reduction, commented Haitham Ahmed, MD, MPH, of the Cleveland Clinic, who was not involved with the trial.
“We have never seen such strong risk reduction with fish oil before. Prior results have been conflicting or showing only minimal benefit,” he told MedPage Today. The effect appears to be even bigger than with PCSK9 inhibitors, and the risk reduction is “even more impressive since these are contemporary patients, on statin therapy, and with controlled LDL already in the [70 mg/dL range].”
Such positive findings make REDUCE-IT stand apart from other trials on triglyceride-lowering agents, according to the authors.
“It is not known whether the lack of benefit from n-3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA). Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n-3 fatty acids,” they said.
“We don’t start to see separation in the curves until at least one year, so the longer study duration here may have been one of the reasons why the trial was so positive compared to previous studies. Also the drug used here represents highly purified EPA which does not lead to LDL elevation and may be superior to other fish oil supplements,” Ahmed suggested.
The STRENGTH trial, which is assessing an alternative fish oil supplement, will show whether the success of REDUCE-IT can be attributed to the compound itself, he said.
Icosapent ethyl is a purified, prescription fish oil known to lower triglyceride levels, and FDA approved for this indication in tandem with a low-fat and low-cholesterol diet. The compound is pure eicosapentaenoic acid (EPA) with no DHA.
Importantly, its observed CV benefits held strong no matter a person’s baseline level of triglycerides or the levels achieved at 1 year, Bhatt’s group noted.
“These observations suggest that at least some of the effect of icosapent ethyl that resulted in a lower risk of ischemic events than that with placebo may be explained by metabolic effects other than a reduction of triglyceride levels,” they said.
Their double-blind trial included over 8,000 patients with established CV disease (or diabetes and other risk factors) who had elevated triglyceride levels despite at least 4 weeks of statin use. Overall, patients had a median age of 64 years and 28.8% were women. Baseline low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol were 75 mg/dL and 40 mg/dL, respectively, and triglycerides were 216 mg/dL. Most patients were receiving treatment for secondary prevention of CV events (70.7%), with the remaining for primary prevention (30.3%).
Of note, subgroup analysis favored the fish-oil group for the primary prevention group but failed to prove significant for both the primary (HR 0.88, 95% CI 0.70-1.10) and second endpoints (HR 0.81, 95% CI 0.62-1.06).
Participants were randomized to 2 g icosapent ethyl twice daily or placebo (mineral oil). One limitation of the study was that the mineral oil could have affected statin absorption in some patients, the investigators cautioned.
By 1 year, the fish oil group had triglyceride levels fall by 18.3% (vs +2.2% for placebo, P<0.001); LDL cholesterol increased by 3.1% (vs +10.2%, P<0.001).
Despite the drop in other CV events, fish-oil patients were more likely to get hospitalized for atrial fibrillation or flutter (3.1% vs 2.1%, P=0.004) and numerically experienced more serious bleeding events (2.7% versus 2.1%, P=0.06).
The assigned treatment made no difference in heart failure.
“The results of the current trial should not be generalized to other n-3 fatty acid preparations — in particular, dietary-supplement preparations of n-3 fatty acid mixtures, which are variable and unregulated and which have not been shown to have clinical benefit,” according to Bhatt and colleagues.
The REDUCE-IT findings come in contrast to the VITAL study, presented at the same meeting, which showed that marine n-3 fatty acid supplementation did not reduce the incidence of major CV events or cancer. Patients had been given a fish-oil capsule containing 840 mg of n-3 fatty acids, including 460 mg of EPA and 380 mg of DHA.
“People should know that they’re not going to get the same kind of doses or benefit unless they’re taking a whole lot of over-the-counter [pills], and we don’t even know if it would have the same benefit to be honest,” said Donald Lloyd-Jones, MD, ScM, of Northwestern Medicine in Chicago.
“The over-the-counter fish-oil pills tend to say 1,000 mg of fish oil — and that’s true, but typically for most of those brands about 300 mg of that is actually omega 3, which is what we care about,” he said. “To get to 4,000 mg of the active ingredients you’d have to take, what, 13 or 14 pills?” he added, noting the potential GI upset of taking so many.
REDUCE-IT was funded by Amarin Pharma.
Bhatt disclosed research funding from Amarin Pharma.
Ahmed has received grant funding from Akcea Therapeutics.
New England Journal of Medicine