麻豆传媒

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PHILADELPHIA -- More time is needed to pin down the mechanism by which icosapent ethyl (Vascepa) works to reduce cardiovascular events, researchers said here.

Changes in atherosclerotic plaque from baseline to 9 months were compared between prescription fish oil and placebo groups in a prespecified interim analysis of the ongoing :

• Low-attenuated plaque: +74% vs +94% (P=0.4692)
• Non-calcified plaque: +35% vs +43% (P=0.0103)
• Calcified plaque: -1% vs +9% (P=0.0010)
• Fibrous plaque: +17% vs +40% (P=0.0109)
• Fibro-fatty plaque: +87% vs +25% (P=0.6500)
• Total plaque: +15% vs +26% (P=0.0004)

Low-attenuated plaque accumulation is the study's primary outcome measure. Missing it in this interim analysis means the trial will have to proceed to the planned 18-month duration, said Matthew Budoff, MD, of UCLA School of Medicine, during a late-breaking trial session here at the American Heart Association (AHA) .

At last year's AHA conference, the REDUCE-IT trial showed that icosapent ethyl reduced cardiovascular death, MI, stroke, coronary revascularization, and unstable angina by 25% over nearly 5 years (23.0% vs 28.3% placebo, HR 0.75, 95% CI 0.68-0.83).

The mechanism behind this was not understood at the time, as it didn't seem to be through triglyceride-lowering or other biomarker-affiliated mechanisms, said AHA program chair Donald Lloyd-Jones, MD, of Northwestern University Feinberg School of Medicine in Chicago, during a press conference.

From EVAPORATE, it looks like icosapent ethyl slows down risky plaque progression without necessarily reversing it. However, the stabilization of which specific plaque components confers clinical benefit remains unknown, Lloyd-Jones said.

Study investigators employed coronary CT angiography to monitor progression of coronary atherosclerosis in 80 statin-treated adults. Eligibility criteria included triglyceride levels 135-499 mg/dL and LDL cholesterol 40-115 mg/dL. Those with severe heart failure and renal insufficiency were excluded.

At the time of the interim analysis, 9-month data were available for 67 participants.

Patients had been randomized to icosapent ethyl 4 mg/d or mineral-oil placebo. The two arms had statistically similar baseline characteristics.

Mineral oil was a notable issue raised from the REDUCE-IT trial, as the control group unexpectedly showed unfavorable biomarker changes over the course of the study. It was hypothesized that mineral oil might have adverse effects limiting the absorption of statins.

The EVAPORATE investigators compared their mineral oil recipients with historical matched controls from GARLIC5, a study that used the same methodology, scanner, and laboratory. Their conclusion: plaque progression was comparable with either mineral oil or a cellulose-based compound as the placebo.

"It's almost impossible to find an inert placebo," said session discussant Stephen Nicholls, MBBS, PhD, of Monash Medicine Health in Melbourne, Australia, citing his own experience in these trials.

Limitations of EVAPORATE include relatively short follow-up and a small sample.

"It will be critical to insure maximal retention of patients on study until final imaging," Nicholls urged.

Budoff noted that this trial marks a departure from his previous plaque studies. Based on recent Japanese optical coherence tomography data, the steering committee had changed the primary endpoint from non-calcified plaque -- the previous standard -- to low-attenuated plaque.

"If we'd stuck with the original endpoint, we would have reported a positive trial," he said during the press conference.

Nevertheless, the results demonstrate a "remarkable consistency across all the endpoints" and the main finding "would have been similarly powered if we used non-calcified or total plaque," according to Budoff.

"I don't think of this study as a failed study," Nicholls said. "It's the interim analysis of a study where we're going to get another opportunity to have another look. That's the advantage of non-invasive imaging."

The FDA is now considering adding an indication of cardiovascular risk reduction to icosapent ethyl's label. Last week, an agency advisory committee voted unanimously that this should be granted.