Icosapent ethyl does not reduce COVID-19 hospitalization, death despite favorable trends
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Treatment with icosapent ethyl was safe and well-tolerated but did not reduce risk for hospitalization or death among COVID-19 outpatients compared with placebo, though researchers observed favorable trends for benefit.
Data from the PREPARE-IT 2 study were presented at the American Heart Association Scientific Sessions.
“We observed a lower rate of the primary outcome with icosapent ethyl vs. placebo, but that difference was not statistically significant,” Rafael Diaz, MD, director of Estudios Clínicos Latino América at Instituto Cardiovascular de Rosario in Argentina, said during a press conference. “The very high loading dose was well-tolerated compared with placebo, although there was a slightly higher rate of discontinuations in the active arm.”
As Healio previously reported, data from a small, first-in-human study presented at the National Lipid Association Scientific Sessions in December 2020 showed icosapent ethyl (Vascepa, Amarin), a pharmaceutical-grade omega-3 fatty acid, reduced levels of inflammatory biomarkers and improved symptoms in patients with COVID-19. The study offered the first evidence of an early anti-inflammatory effect of icosapent ethyl in symptomatic patients. The PREPARE-IT 1 study, presented at the European Society of Cardiology Congress in August, demonstrated high-dose icosapent ethyl for 60 days did not prevent incident SARS-CoV-2 infection among healthy participants who did not have prior known infection, with or without COVID-19 vaccination.
Nonsignificant, favorable trend observed
For PREPARE-IT 2, researchers assessed if icosapent ethyl might be effective in reducing risk for COVID-19-related morbidity or mortality in symptomatic nonhospitalized patients. They also examined the safety and tolerability of a high loading dose.
The study included 2,052 adults aged at least 40 years with a confirmed positive COVID-19 diagnosis no more than 7 days from onset of symptoms and without a clear indication for hospitalization, randomly assigned to icosapent ethyl (n = 1,010) or placebo (n = 1,042). Participants in the icosapent ethyl arm received an initial loading dose of 8 g daily for the first 3 days — double the FDA-approved dose — followed by a 4-g daily dose from day 4 to day 29. The primary endpoint was COVID-19-related hospitalization or death at 28 days. A subgroup of patients completed the influenza patient-reported outcome (FLU-PRO) score, a 32-item score across six domains, at baseline and again at 28 days.
Compared with placebo, researchers observed fewer COVID-19 hospitalizations or deaths among participants in the icosapent ethyl arm (11.16% vs. 13.69%); however, the HR of 0.84 did not reach statistical significance (95% CI, 0.65-1.08; P = .166).
Across secondary outcomes, researchers also observed numerically fewer COVID-19 hospitalizations, deaths or new requirements for mechanical ventilation in the icosapent ethyl arm vs. placebo (OR for COVID-19 hospitalization or death = 0.78; 95% CI, 0.55-1.12; P = .18; OR for new mechanical ventilation = 0.76; 95% CI, 0.26-2.08; P = .648). Four patients in the icosapent ethyl arm and eight patients in the placebo arm died (OR = 0.52; 95% CI, 0.11-1.95; P = .388).
“All secondary outcomes were nonsignificant, although all trended in the same [positive] direction,” Diaz said.
Icosapent ethyl was safe and well tolerated, with no between-group differences in adverse events. There was no atrial fibrillation/flutter or major bleeding observed in either group.
Diaz said larger, randomized trials adequately powered for a 15% relative risk reduction are needed to establish whether icosapent ethyl may have a role in the management of COVID-positive outpatients.
Demonstrating safety
The PREPARE-IT 2 study was an opportunity for investigators to assess an already-approved treatment that could potentially be easily deployed and repurposed for COVID-19-positive outpatients, a group without many treatment options, according to Cardiology Today Intervention Section Editor Deepak L. Bhatt, MD, MPH, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School.
“We found that the loading dose of icosapent ethyl was well-tolerated, and it was not associated with many adverse events vs. placebo,” Bhatt, also the PREPARE-IT 2 study chair, said in an interview. “In the REDUCE-IT study, we did see an increased risk for bleeding and atrial fibrillation in the icosapent ethyl group, something we did not see here with COVID-19 outpatients.”
While the primary outcome was not significant, “directionally, it looked like there might be a positive benefit, in a trial that ended up being underpowered,” Bhatt said. "This would need to be confirmed in a large, adequately powered trial."
“It is useful to show this drug was not misbehaving in people who were actually sick, and that the loading dose was very well tolerated,” Bhatt said. “This opens the door in the future for studying the drug with the loading dose we used in PREPARE-IT 2 in ill patients with acute MI or stroke, for example.”
Perspective
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Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC
Eicosapentaenoic acid is an interesting compound. It does lower triglycerides, but in the REDUCE-IT trial, the 25% reduction in major adverse CV events was far greater than what we would expect to see with just triglyceride lowering. There are likely anti-inflammatory and antithrombic effects with icosapent ethyl. Inflammation also plays a causative role in symptomatic COVID-19. An activation of the inflammatory cascade can lead to secondary organ damage, including cardiac injury.
PREPARE-IT 2 was, overall, a null study. However, if you look at the primary outcome, there was a reduction in COVID-19 hospitalization and death of 16%, so the HR did go in a favorable direction. A factor to keep in mind is these were patients who were COVID-19-positive but not that sick. Anyone already hospitalized was excluded. We have gotten better at treating people with COVID-19 as the pandemic progressed. The rate of hospitalization was lower than what the trial was powered for.
There are some key takeaways. There have been a lot of concerns about AF in these omega-3 fatty acid trials. While this was a 28-day study, there was no increased risk for AF with a loading dose that was twice as high, and no major bleeding. This reaffirms the safety of icosapent ethyl.
Where do we go from here? A larger randomized clinical trial would be needed to see a benefit with icosapent ethyl, but I don’t think that is feasible. This study likely will not affect clinical practice right now. Vaccination remains the best strategy to prevent severe COVID-19.
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Diaz R, et al. LBS.06. Fish Oil and Cholesterol: Recipes for CVD Prevention? Presented at: American Heart Association Scientific Sessions; Nov. 13-15, 2021 (virtual meeting).
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