Icosapent Ethyl Shows Signal but Not Significance for Clinical Improvement in COVID-19 Outpatients – The PREPARE-IT 2 Trial

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By Jamie Diamond, MD on

Key Points:

  • Icosapent ethyl (IPE) had previously shown a signal for improvement in COVID-19 symptoms and decreased inflammatory marker levels in COVID-19 patients
  • PREPARE-IT 2 sought to determine if icosapent ethyl would reduce planned COVID-19-related hospitalizations or mortality in patients with a positive diagnosis of COVID-19 assessed up to 28 days
  • PREPARE-IT 2 was a pragmatic trial which randomized >2,000 patients to very high dose EPA (8 grams/day) or placebo
  • There was a neutral result regarding prevention of COVID-19-related hospitalization or mortality at 28 days, though trend towards improved outcomes amongst all clinical endpoints in the IPE group
  • The safety and tolerability of high-dose IPE was again established
  • Further studies determining potential effects of IPE in COVID-19 outpatients are warranted

A host of tools have been rapidly developed or repurposed to combat the damaging effects of novel coronavirus disease 2019 (COVID-19) on infected patients. Icosapent ethyl (IPE), a high-dose form of eicosapentaenoic acid (EPA) and a known anti-inflammatory medication, is a safe, well-tolerated oral therapy known to be effective in improving outcomes in patients with established cardiovascular disease or those with diabetes and one or more additional risk factor (Bhatt DL, et al. “Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia”. The New England Journal of Medicine. 2018. epub 2018-11-10:1-12). Furthermore, the VASCEPA COVID-19 CardioLink-9 trial established that of 50 COVID-19 patients taking IPE, many had a significant improvement in validated patient-reported FLU-PRO score symptoms and decreased inflammatory biomarker at 14 days. Whether IPE could reduce infection rates and subsequent morbidity and mortality among high-risk outpatients with COVID-19 was however not yet confirmed in a randomized trial.

PREPARE-IT (NCT04460651) 1 was a pragmatic, double-blind, placebo-controlled trial to investigate whether COVID-19 could be prevented with EPA in outpatient adults who had no clinical evidence of the infection, never previously diagnosed with COVID-19 and were unvaccinated. The study, presented at the virtual European Society of Cardiology Congress 2021, found that IPE did not prevent SARS-COV-2 viral infection. It did however establish the safety and tolerability of an 8 gram per day loading dose of IPE.

In order to evaluate the effects of IPE in COVID-19 positive non-hospitalized patients, PREPARE-IT 2 was presented at the 2021 AHA virtual Scientific Sessions by Rafael Díaz, MD (ECLA, Argentina). PREPARE-IT 2 was a pragmatic, web-based trial developed with the primary aim of evaluating if IPE would reduce COVID-19 related hospitalization (either indication for hospitalization per the blinded investigator or actual hospitalization) or death in COVID-19 positive outpatients within 28 days. Patients allocated to the active arm received 8 grams per day of IPE for the first three days followed by 4 grams per day from days 4 through 28. Only patients 40 years of age or older, with COVID-19 confirmed on RT-PCR or rapid test, with no more than 7 days since symptom onset and without clear indication for hospitalization were included. It is important to note that hospitalized patients or those patients with a clear indication for hospitalization related to their COVID-19 infection were excluded from the study group.

The PREPARE-IT 2 trial ultimately included 2,052 patients and found that COVID-19-related hospitalization or death was present in 13.7% of the placebo group (135 patients) and 11.2% of the group receiving IPE (110 patients) with a hazard ratio of 0.84 (95% CI 0.65-1.08, p=0.17). The secondary outcomes of COVID-19 hospitalization, COVID-19 death, hospital admission or death at day 28, mechanical ventilation requirement, total events (non-fatal myocardial infarction, stroke of death) and total mortality were also similar between the two groups.  Dr. Díaz notes that though none of the findings are statistically significant, there is a consistent trend towards a benefit in the IPE group in all outcomes that were assessed. The safety was noted to be well-tolerated with no difference in any safety outcomes and no increased atrial fibrillation or bleeding in the IPE group. There was however significantly more discontinuation reported in the active as compared to placebo group.

During the discussion at the AHA virtual Scientific Sessions the moderators and lead investigator agree that large-scale patient enrollment and engagement, particularly during the COVID-19 pandemic, was a significant challenge for this and other pragmatic trials. Dr. Diaz concludes that larger, randomized trails powered for a 15% relative risk reduction (as opposed to 30% in this trial) with IPE are needed to establish whether it may have a role in the management of COVID-19 positive outpatients.

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