High doses (4-g daily) of the omega-3 oil eicosapentaenoic acid (EPA) have shown a large benefit on cardiovascular events in the randomized, double-blind REDUCE-IT trial.

Top-line results of the trial were announced yesterday in a press release by the sponsor, Amarin, which manufactures the high-dose EPA product under the brand name Vascepa.

The study involved 8179 patients from 11 countries who were at elevated cardiovascular risk (had a previous cardiovascular event or diabetes with one additional risk factor) and had raised triglyceride levels. All participants, who were already taking a statin, were randomized to 4 g of the pure EPA product daily or placebo.

After a median follow-up of 4.9 years, there was an approximately 25% relative risk reduction in the primary endpoint of first occurrence of a major adverse cardiovascular event — any one of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization — in the EPA group, which was highly significant (P < .001), the company reported.

There were also "robust demonstrations of efficacy across multiple secondary endpoints," the company's statement said.

In terms of safety, the high-dose EPA was said to be "well tolerated," with similar proportions of patients experiencing adverse events and serious adverse events in the active and placebo treatment groups.

More details of REDUCE-IT will be presented by principal investigator Deepak L. Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts, at the American Heart Association (AHA) Scientific Sessions 2018 on November 10 in Chicago, Illinois.

During a company conference call, John Thero, president and chief executive officer of Amarin, referred to the benefit of the high-dose EPA as "huge" and "exceeding all expectations."

"The 25% relative risk reduction in major cardiovascular events seen with Vascepa is comparable to that seen with atorvastatin, one of the most successful drugs of all time," he said, "and the benefit of Vascepa was seen on top of statin therapy therefore is addressing an unmet medical need."

"Clearly, lowering low-density lipoprotein cholesterol (LDL-C) alone is not enough," he said. "That can give a relative risk reduction of 25% to 35%, but this leaves a residual risk of 65% to 75%. The additional 25% relative risk reduction seen in this study is the single most impressive advance for preventative cardiovascular drug therapy since the advent of the statins."

The product is also easy to use, taken orally, safe, and inexpensive compared with other branded cardiovascular drugs, Thero added, "and it now has the potential to be used in millions of patients on top of statin therapy for additional cardiovascular risk reduction."

An entry criterion for the REDUCE-IT study were LDL-C levels of 41 to 100 mg/dL (median was 75 mg/dL). Patients also needed to have persistently elevated triglyceride levels of 150 to 499 mg/dL (median was 216 mg/dL). Thero estimated that 60 to 70 million people in the United States have triglyceride levels in this range.

Vascepa is currently approved for use in patients with triglyceride levels over 500 mg/dL. The company plans to apply to the US Food and Drug Administration for this new indication based on results of REDUCE-IT in early 2019.

In an interview with Medscape Medical News, REDUCE-IT investigator Christie Ballantyne, MD, Baylor College of Medicine, Houston, Texas, said it was very important to understand the patient population enrolled in the study.

He noted that "70% of patients were secondary prevention and 30% high-risk primary prevention (had diabetes and one additional risk factor). All patients had baseline triglycerides over 150 mg/dL on statin therapy. This is very different from other studies which did not include elevated triglycerides as an entry criterion."

"It's hard to believe that in this era of precision medicine there has never been a study before specifically addressing whether the lowering of triglycerides is beneficial in patients with elevated levels," Ballantyne commented.

He also pointed out that the dose of EPA used was probably a key factor in the benefit seen. "We used a high dose (4-g daily) of EPA alone, whereas most previous studies of omega-3 oils (most recently in the ASCEND trial) have used much lower doses of mixed oils. The only prior study that used EPA alone at higher doses was the Japanese JELIS trial, which used 1.8-g daily and also showed benefit."

Ballantyne noted that the JELIS trial did not stipulate that patients had to have raised triglyceride levels but the most benefit was seen in those who did. "The REDUCE-IT trial confirms the results of the JELIS trial but REDUCE-IT has a more rigorous design and a different patient population."

Ballantyne was reluctant to speculate on the clinical implications of the results at the present time. "I will let the clinicians at the AHA meeting decide on the clinical relevance of the data when they see it for themselves in more detail."

But he did say that "the study was powered for a 15% relative risk reduction, and we achieved a 25% relative risk reduction. Whenever you exceed the benefit aimed for, you get excited by the results."

"I have been in this field for a long time and witnessed many failures of drugs aiming to reduce cardiovascular risk. It will be great to get these data out to the cardiology community at AHA."

Commenting for Medscape Medical News, Henry Ginsberg, MD, University of Columbia, New York City, who was not involved in the study, said the reported results are "fascinating and important."

"I really didn't think that fish oils would show such a strong effect. I was guessing they might achieve a 10% to 12% benefit at the most. So this is terrifically exciting," he said. "It will change practice."

He agreed that the dosage was probably a key issue. "Previous fish oil studies have mainly used doses of around 1 g daily of mixed omega-3 oils and have not shown benefits. This trial has used 4 g of pure EPA," he noted. "The JELIS trial used 1.8-g daily of EPA, which showed a 19% benefit and was significant for secondary prevention but not for primary prevention."

"The JELIS study did not stipulate raised triglycerides for entry and the drop in triglycerides was modest," he noted, "but a post-hoc analysis showed a greater benefit in those patients with raised triglycerides at baseline."

Although lowering triglycerides with high-dose EPA was the main focus of the REDUCE-IT trial, Ballantyne noted that high doses of EPA have been shown to have other beneficial effects.

"Previous studies have suggested that in addition to lowering triglycerides, EPA has a favorable effect on inflammation and several other markers of atherosclerosis," he said. "Basically we don't know the mechanism. It may be the reduction in triglycerides but it also appears to do lots of other good things."

Thero added, "We view the JELIS results as supportive for using EPA to benefit patients without raised triglycerides as well as those with raised triglycerides. It suggests that the benefits of EPA are not brought about by triglyceride reduction alone."

Ginsberg estimated that about 30% of the US population have triglyceride levels above 150 mg/dL. "This percentage would be higher in a secondary prevention population — possibly 40%," he said.

Another trial of high-dose omega-3 oils for cardiovascular event reduction is underway. The STRENGTH trial is using a combination EPA/docosahexaenoic acid product with a total of 4-g omega-3 oils daily in patients with triglycerides over 200 mg/dL. Results are due out next year.

"The REDUCE-IT trial has shown a strong result," lead investigator of the STRENGTH trial, Steve Nissen, MD, Cleveland Clinic, Ohio, commented to Medscape Medical News.

"I am not surprised that it was successful," Nissen said. "Prior studies used small dosages of fish oil (1 g) and studied a broad group of patients. Both REDUCE-IT and STRENGTH treated patients with high triglycerides with full doses (4 g)."

The authors have reported no relevant financial relationships.

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