番茄社区

NEW ORLEANS -- A prescription-grade fish oil was able to prevent multiple cardiovascular events, not just first events, according to a secondary analysis of REDUCE-IT trial data.

Patients randomized to had significantly fewer total events over 4.9 years of follow-up relative to those assigned to placebo (RR 0.70, 95% CI 0.62-0.78), according to Deepak Bhatt, MD, of Brigham and Women's Hospital in Boston, here at the American College of Cardiology's annual conference.

Broken down, that 30% event reduction was observed for the primary endpoint of combined cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, and hospitalization for unstable angina in:

• First events: HR 0.75, 95% CI 0.68-0.83
• Second events: HR 0.68, 95% CI 0.60-0.78
• Third events: HR 0.69, 95% CI 0.59-0.82
• Fourth and subsequent events: RR 0.52, 95% CI 0.38-0.70

Results were simultaneously published online in the .

The REDUCE-IT investigators had previously reported that icosapent ethyl recipients experienced fewer first events (23.0% vs 28.3%, HR 0.75, 95% CI 0.68-0.83), which were the study's .

Now, accounting for those who may have survived their first event but gone on to have subsequent ischemic events, the benefits of fish oil still held up. Total rates of first and subsequent events, including cardiovascular death, MI, and stroke, yielded another advantage to the icosapent ethyl group (RR 0.72, 95% CI 0.63-0.82).

"The implication is that this sort of analysis should be done in all trials that have MACE [major adverse cardiovascular event] outcomes," commented Eileen Handberg, PhD, ARNP-BC, at a press conference. She called REDUCE-IT a "paradigm shift for clinical trial reporting."

“Several approaches to recurrent event analyses have been tested. All have limitations, as complex assumptions are made in statistical modelling. One concern is overestimation of the treatment effect, and another is how best to manage the competing risk of death,” said Sanjay Kaul, MD, of Cedars-Sinai Medical Center in Los Angeles, who was not involved with the trial.

“The results of this analysis show that the benefits [of icosapent ethyl] are preserved, and to some degree amplified, when all events are accounted for, thereby capturing the totality of treatment benefit,” he told 番茄社区.

Participants in the double-blind study were 8,179 patients randomized to icosapent ethyl or placebo. These were adults with established cardiovascular disease (or diabetes with one cardiovascular disease risk factor), with elevated triglycerides and LDL cholesterol who were told to stay on statin therapy.

That patients were still on statins is what makes the 30% risk reduction striking, according to Michael Miller, MD, of the University of Maryland School of Medicine, who was on the steering committee for the trial. He cited risk reductions of 7% with statin plus ezetimibe and 15% with PCSK9 inhibition, as found in prior studies.

Icosapent ethyl is pure eicosapentaenoic acid (EPA) with no docosahexaenoic acid (DHA).

"It's efficacious, and the results are unprecedented," Miller told 番茄社区 (an an Amarin representative was present during the interview).

The fish oil and placebo arms in REDUCE-IT shared similar baseline characteristics and medications taken. There was some waning in study drug adherence over follow-up, albeit to the same extent between groups.

First events accounted for 55% of all events (n=2,909).

In the case where a patient had multiple events occur on the same day, Bhatt's group opted for a conservative statistical approach in which they counted only one cardiovascular event that day. This was done post hoc, with the prespecified full dataset showing "effect sizes at least as large, and more extreme p values," he emphasized.

Bhatt added that cost-effectiveness analyses for icosapent ethyl are now underway.

"The total event data from REDUCE-IT are impressive, clinically relevant, and extend what we know about targeting patients with elevated triglycerides. Exciting ongoing trials such as STRENGTH and PROMINENT will teach us about the consistency of triglyceride targeting as well as a great deal about mechanisms of effect," commented Paul Ridker, MD, also of Brigham and Women's Hospital, who was not involved with the trial.

is a trial comparing another fish oil preparation, combining EPA and DHA (Epanova), to statin therapy in patients with high triglycerides. Meanwhile, the question in is whether pemafibrate (Parmodia) can bring down event rates for those with high triglycerides and diabetes.

Vascepa, you may recall, was at the center of a dispute with the FDA over Amarin's marketing of the product. After a court battle, the agency agreed to allow Amarin to distribute "truthful, non-misleading information" about the product's event-prevention effects without getting a formal expansion of its approved indications. In exchange, Amarin promised to finish the REDUCE-IT trial and report its findings -- on which the firm has now delivered.

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