REDUCE-IT: Prescription Fish Oil Prevents CV Events in Patients With High Triglycerides

CHICAGO, IL—Icosapent ethyl (Vascepa; Amarin), a prescription omega-3 fatty acid formulation, reduces cardiovascular events in statin-treated patients with high triglyceride levels and either established cardiovascular disease or diabetes plus risk factors, full results of the REDUCE-IT trial show.

Through a median follow-up of 4.9 years, the primary MACE endpoint (CV death, MI, stroke, coronary revascularization, or unstable angina) occurred in 17.2% of patients treated with icosapent ethyl and 22.0% of those who received placebo (HR 0.75; 95% CI 0.68-0.83), Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), reported here at the American Heart Association (AHA) 2018 Scientific Sessions. That works out to a number needed to treat of 21.

Icosapent ethyl also reduced a key secondary composite endpoint of CV death, MI, or stroke (11.2% vs 14.8%; HR 0.74; 95% CI 0.65-0.83), with a number needed to treat of 28.

The results, published simultaneously online in the New England Journal of Medicine, showed consistent effects in both the primary and secondary prevention cohorts. Topline results were released in September.

At a press conference, Bhatt made it clear that the benefits seen with icosapent ethyl in REDUCE-IT should not be extrapolated to the myriad over-the-counter fish oil supplements available to the public.

“The first message, at least as far as omega-3 fatty acids that I have been giving patients and will keep giving is don’t waste your money on those supplements. They are safe, but they don’t provide any cardiovascular or other demonstrable benefits,” he said, adding that these supplements, which often contain a mix of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are not regulated. In this trial, patients in the intervention group received icosapent ethyl, a purified ethyl ester of EPA. It is approved by the US Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL).

Commenting for TCTMD, Pradeep Natarajan, MD (Massachusetts General Hospital, Boston), called the results exciting because they highlight a new treatment to reduce the residual CV risk seen in patients treated with statins and other types of medications, with a relative risk reduction similar to what has been seen in statin trials.

Asked whether he’d consider using icosapent ethyl in more of his patients based on these results, Natarajan said that it’s important to recognize some potential downsides with the agent, including the observed absolute increase in A-fib-related hospitalizations of about 1%, which is “not necessarily trivial,” as well as cost.

“But aside from that, for patients who have well-controlled LDL cholesterol who are otherwise on guideline-appropriate medicine, this is an excellent option for those with persistent residual hypertriglyceridemia,” Natarajan said. “I’m very encouraged by the results.”

Benefits Consistent Across Subgroups

Bhatt noted that the weight of the evidence suggests that high levels of triglycerides are causally related to cardiovascular risk. Even so, nearly all prior trials evaluating a variety of triglyceride-lowering therapies—including extended-release niacin, fibrates, cholesteryl ester transfer protein inhibitors, and omega-3 fatty acids—have failed show reductions in cardiovascular events. That includes the ASCEND trial, which evaluated the impact of omega-3 fatty acids at a dose of 1 g/day, and the VITAL trial, which also was reported here at AHA.

One exception was the JELIS trial, in which omega-3 fatty acids given at a dose of 1.8 g/day lowered cardiovascular risk in patients with hypercholesterolemia. That trial was critiqued, Bhatt said, in that it was open-label and involved Japanese patients with high average fish intake and relatively low statin use.

The REDUCE-IT trial was designed to bolster those findings. Conducted at 473 sites in 11 countries, the trial randomized 8,179 patients who were at least 45 years old and had established CVD (secondary prevention cohort) or who were at least 50 years old and had diabetes and at least one additional CVD risk factor (primary prevention cohort). Fasting triglyceride levels had to be at least 135 mg/dL but less than 500 mg/dL, and LDL cholesterol levels had to be greater than 40 mg/dL but no higher than 100 mg/dL on stable statin therapy. Overall, mean patient age was 64, and 29% were women. Most patients (71%) were being treated for secondary prevention.

Overall, the median triglyceride and LDL cholesterol levels were 216 and 75 mg/dL, respectively. In the first year, triglycerides were reduced by a median of 39 mg/dL in the icosapent ethyl group, compared with a median increase of 4.5 mg/dL in the placebo group. LDL cholesterol increased slightly in both groups.

The impact of icosapent ethyl on clinical outcomes was largely consistent across subgroups. Of note, benefits were seen in both primary and secondary prevention cohorts and irrespective of baseline or attained triglyceride level.

Hierarchical testing showed reductions in all components of the primary composite endpoint, with a relative 20% reduction in CV death (4.3% vs 5.2%; HR 0.80; 95% CI 0.66-0.98). All-cause mortality was numerically—but not significantly—lower in the icosapent ethyl group (6.7% vs 7.6%; HR 0.87; 95% CI 0.74-1.02).

Overall adverse events were similar in both groups. Serious adverse bleeding was numerically higher with active treatment (2.7% vs 2.1%; P = 0.06), but there were no fatal bleeds in either group and no between-group difference in hemorrhagic stroke. Diarrhea and anemia were more frequent in the placebo group, whereas peripheral edema, constipation, and A-fib were more common in the icosapent ethyl group. Hospitalization for A-fib or atrial flutter was significantly higher in the intervention arm (3.1% vs 2.1%; P = 0.004).

Bhatt said he would have been worried more about the A-fib finding if stroke had also been increased, but that was reduced along with other cardiovascular events by icosapent ethyl.

Carl Orringer, MD (University of Miami, FL), who served as a discussant for REDUCE-IT, also did not seem too concerned, saying at the press conference that the difference in A-fib “should not prevent a physician from prescribing the drug because of the tremendous benefit that was seen in those who took the agent on top of moderate- or high-intensity statins.”

Placebo Problems?

Steven Nissen, MD (Cleveland Clinic, OH), who is heading the STRENGTH trial of another omega-3 fatty acid formulation, said he had some concerns with REDUCE-IT. In particular, the placebo capsule contained mineral oil, which has been shown to affect absorption of certain drugs, including statins.

There is evidence of that happening in this trial, he said, with a 5-mg/dL greater increase in LDL cholesterol in the placebo group over the first year of treatment. In addition, C-reactive protein levels rose in the placebo arm, which could also be an effect of the mineral oil.

“And so we’re left with a dilemma here,” Nissen said. “We can’t be absolutely certain that the favorable results seen were not due at least in part to the fact that the placebo here is actually having toxicity that makes the active arm look better. That’s the big concern.”

For his part, Natarajan said that the mineral oil issue likely did not have a major impact on the findings. The modest increase in LDL cholesterol would not account for the 25% relative risk reduction in the primary endpoint with icosapent ethyl, he said, adding that a post hoc analysis showing consistent effects regardless of whether patients in the placebo arm had an increase in LDL cholesterol or either no change or a decrease in levels was reassuring.

Nissen said additional trials are likely needed to address these concerns, however. He noted that the STRENGTH trial, which is evaluating an omega-3-carboxylic acid formulation (Epanova; AstraZeneca) and has enrolled more than 13,000 patients with hypertriglyceridemia, low HDL cholesterol, and a high risk for CVD, will probably wrap up next year. Other ongoing trials, such as RESPECT-EPA in Japan and EVAPORATE, will provide information as well.

Mechanisms Unknown

Further research is also needed to provide insight into how icosapent ethyl is improving outcomes. Reductions in cardiovascular events were seen across groups defined by baseline and attained triglyceride levels, which suggests mechanisms beyond triglyceride-lowering. Icosapent ethyl may also have antithrombotic, anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing effects. Bhatt said biomarker and genetic analyses are planned.

Regardless of the mechanism, Orringer said, “REDUCE-IT supports the position that icosapent ethyl is safe, well-tolerated, and reduces the likelihood of cardiovascular events in stable, high-risk hypertriglyceridemia patients taking evidence-based statin therapy.”

This is the first study that evaluated this approach in patients with hypertriglyceridemia, he added, so “we have a very important addition to the potential therapeutic armamentarium for these patients.”