Final EVAPORATE Results for Vascepa Raise Eyebrows

Patrice Wendling

September 04, 2020

Final 18-month results of the EVAPORATE trial suggest icosapent ethyl (Vascepa) provides even greater slowing of coronary plaque progression when added to statins for patients with high triglyceride levels, but not all cardiologists are convinced.

The study was designed to explore a potential mechanism behind the cardiovascular event reduction in REDUCE-IT. Previously reported interim results showed that after 9 months, the pharmaceutical-grade omega-3 fatty acid formation significantly slowed the progression of several plaque types but not the primary endpoint of change in low-attenuation plaque volume on multidetector CT.

From baseline to 18-month follow-up, however, the primary endpoint was significantly reduced by 17% in the icosapent ethyl group, whereas low-attenuation plaque volumes increased by 109% in the placebo group (P = .0061).

Significant declines were also seen with icosapent ethyl 4 g/d vs the mineral oil placebo for all other plaque types except dense calcium after adjustment for age, sex, diabetes, hypertension, and triglyceride levels at baseline:

  • dense calcium: -1% vs 15% (P = .0531)

  • fibro-fatty: -34% vs 32% (P = .0002)

  • fibrous: -20% vs 1% (P = .0028)

  • noncalcified: -19% vs 9% (P = .0005)

  • total plaque: -9% vs 11% (P = .0019)

The results parallel nicely with recent clinical data from REDUCE-IT REVASC, in which icosapent ethyl 4 g/d provided a very early benefit on first revascularization events that reached statistical significance after only 11 months (hazard ratio, 0.66), principal investigator Matthew Budoff, MD, director of cardiac CT at Harbor-UCLA Medical Center in Torrance, California, said during the virtual European Society of Cardiology Congress 2020.

The findings were also published simultaneously in the European Heart Journal and quickly prompted a flurry of comments on social media.

Some were supportive. Harvard University's Christopher Cannon, MD, University of Pennsylvania lipidologist Dan Soffer, MD, and Intermountain Heart Institute researcher Viet Le, MPAS, PA, took to Twitter to praise Budoff and the final results of the mechanistic study. Soffer called the study "elegant," while Cannon said the results provide "important mechanistic data on plaque character."

Others were highly critical, including a poll questioning whether the article should be retracted or revised.

Ibrahim H. Tanboga, MD, PhD, a cardiology professor and biostatistician at Hisar Intercontinental Hospital in Istanbul, Turkey, questioned how the longitudinal change in low-attenuation plaque was possible clinically; his plot of the data showed these lesions getting worse in both arms before getting better in both arms.

A more volatile exchange concerned whether there were differences in the baseline characteristics between the two groups and whether the data might have been unblinded.

https://twitter.com/ProfDFrancis/status/1300003801496248320?s=20

 

"I am sympathetic to the boss of a big laboratory [who] might not know how every step of the process was done and therefore might not be aware of opportunities for accidental bias. This can easily happen in a large and active department," Darrel Francis, MD, professor of cardiology at the National Heart and Lung Institute, Imperial College, London, United Kingdom, said in an interview.

An alternative explanation proffered on Twitter was that the interim analysis found no significant differences in baseline measures because it used nonparametric tests, whereas log transformation was applied to the final data. In any event, the tweets prompted a sharp rebuke from Budoff.

Francis raised another point of contention on Twitter regarding the degree of plaque progression in the placebo group.

https://twitter.com/ProfDFrancis/status/1300098439884271616

Speaking to theheart.org | Medscape Cardiology, Francis pointed out that the final data represent the percentage change in the logarithm, not the actual percentage change in atheroma. So the increase in total atheroma volume in the placebo arm is not 11% but rather a scaling-up by 100.4 or 2.51, in other words, 151%.

He also offered a "less subtle feature of possible erroneous data," in that the abstract reports that low-attenuation plaque "more than doubles" in 18 months, which he described as a "ghastly supercharged version of Moore's law for atheroma, instead of microchips."

So "either it's a mistake in the measurement or the placebo is harmful, because I can't see how this is sustainable," he said. "Why isn't everyone dead from coronary disease?"

Concerns were raised previously over the possibility that the mineral oil placebo used in both EVAPORATE and REDUCE-IT could be having ill effects, notably, by increasing low-density cholesterol and C-reactive protein levels.

In an interview, Steven Nissen, MD, who is chair of cardiovascular medicine at the Cleveland Clinic, Cleveland, Ohio, and has been among the critics of the mineral oil placebo, also questioned the plaque progression over the 18 months.

"I've published more than dozen regression/progression trials, and we have never seen anything like this in a placebo group, ever," he said. "If this was a clean placebo, why would this happen in a short amount of time?

"I'm concerned this is all about an increase, in the case of REDUCE-IT, in morbidity and mortality in the placebo group, and in the EVAPORATE trial, an increase in plaque in the placebo group," Nissen said. "So this raises serious doubts about whether there is any benefit to icosapent ethyl."

Asked about the 109% increase, Budoff told theheart.org | Medscape Cardiology that low-attenuation plaque represents a much smaller quantity of overall plaque volume. "So the percentages might be exaggerated if you look at just percentage change because they're small volumes."

He also noted that previous trials that evaluated atherosclerosis progression used intravascular ultrasound (IVUS), whereas EVAPORATE is the first to make the transition to CT angiography-based analysis of plaque progression.

"I would point out that Dr Nissen has only worked on intravascular ultrasound, which, while it's parallel in its ability to measure plaque, measures different volumes and measures it in a totally different way," said Budoff. "So I don't think we can directly compare the results of CT angiography to Dr Nissen's examples of IVUS."

During his presentation, Budoff highlighted their recent data showing a similar rate of plaque progression between the mineral oil placebo in EVAPORATE and a cellulose-based placebo in the Garlic5 study. "So we have high confidence that the benefits seen in this trial with icosapent ethyl represent icosapent ethyl's beneficial effects on atherosclerosis and not harm of mineral oil," he said.

Exactly how icosapent ethyl is slowing atherosclerosis, however, is not fully known, Budoff said in an interview. "It might be inflammation and oxidation; those have both been shown to be better with icosapent ethyl, but I don't think we fully understand the implications of these results."

Budoff dismissed tweets that suggest the data might have been unblinded as unprofessional and said they are requesting that Imperial College have Francis cease and desist.

"He doesn't have the actual data, so there is no way to do statistics without the dataset. The whole thing is inappropriate," Budoff said.

Amarin Pharma provided funding and drug for the trial. Budoff has received research funding from and has served as a speaker for Amarin Pharma, Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Pfizer and has served as a speaker for Bristol-Myers Squibb. Francis has disclosed no relevant financial relationships..

Eur Heart J. Published online August 29, 2020. Full text

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.orgMedscape Cardiology, join us on Twitter and Facebook.

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