Two Swings, Two Misses With Colchicine, Vascepa in COVID-19

Patrice Wendling

August 31, 2021

The anti-inflammatory agents colchicine and icosapent ethyl (Vascepa; Amarin) failed to provide substantial benefits in separate randomized COVID-19 trials.

Both were reported at the European Society of Cardiology (ESC) Congress 2021.

The open-label ECLA PHRI COLCOVID trial randomized 1277 hospitalized adults (mean age 62 years) to usual care alone or with colchicine at a loading dose of 1.5 mg for 2 hours followed by 0.5 mg on day 1 and then 0.5 mg twice daily for 14 days or until discharge.

The investigators hypothesized that colchicine, which is widely used to treat gout and other inflammatory conditions, might modulate the hyperinflammatory syndrome, or cytokine storm, associated with COVID-19.

Results showed that the need for mechanical ventilation or death occurred in 25.0% of patients receiving colchicine and 28.8% with usual care (P = .08).

The coprimary endpoint of death at 28 days was also not significantly different between groups (20.5% vs 22.2%), principal investigator Rafael Diaz, MD, said in a late-breaking COVID-19 trials session at the digital congress.

Among the secondary outcomes at 28 days, colchicine significantly reduced the incidence of new intubation or death from respiratory failure from 27.0% to 22.3% (hazard ratio, 0.79; 95% confidence interval, 0.63 - 0.99) but not mortality from respiratory failure (19.5% vs 16.8%).

The only important adverse effect was severe diarrhea, which was reported in 11.3% of the colchicine group vs 4.5% in the control group, said Diaz, director of Estudios Clínicos Latino América (ECLA), Rosario, Argentina.

The results are consistent with those from the massive RECOVERY trial, which earlier this year stopped enrollment in the colchicine arm for lack of efficacy in patients hospitalized with COVID-19, and COLCORONA, which missed its primary endpoint using colchicine among nonhospitalized adults with COVID-19.

Session chair and COLCORONA principal investigator Jean-Claude Tardif, MD, pointed out that, as clinicians, it's fairly uncommon to combine systemic steroids with colchicine, which was the case in 92% of patients in ECLA PHRI COLCOVID.

"I think it is an inherent limitation of testing colchicine on top of steroids," said Tardif, Montreal Heart Institute, Canada.

Icosapent Ethyl in PREPARE-IT

Diaz returned in the ESC session to present the results of the PREPARE-IT trial, which tested whether icosapent ethyl — at a loading dose of 8 grams (4 capsules) for the first 3 days and 4 g/d on days 4 to 60 — could reduce the risk for SARS-CoV-2 infection in 2041 healthcare and other public workers in Argentina at high risk for infection (mean age 40.5 years).

Vascepa was approved in 2012 for the reduction of elevated triglyceride levels, with an added indication in 2019 to reduce cardiovascular (CV) events in people with elevated triglycerides and established CV disease or diabetes with other CV risk factors.

The rationale for using the high-dose prescription eicosapentaenoic acid (EPA) preparation includes its anti-inflammatory and antithrombotic effects, and that unsaturated fatty acids, especially EPA, might inactivate the enveloped virus, he explained.

Among 1712 participants followed for up to 60 days, however, the SARS-CoV-2 infection rate was 7.9% with icosapent ethyl vs 7.1% with a mineral oil placebo (P = .58).

There were also no significant changes from baseline in the icosapent ethyl and placebo groups for the secondary outcomes of high-sensitivity C-reactive protein (0 vs 0), triglycerides (median -2 mg/dL vs 7 mg/dL), or Influenza Patient-Reported Outcome (FLU-PRO) questionnaire scores (median 0.01 vs 0.03).

The use of a mineral oil placebo has been the subject of controversy in previous fish oil trials, but, Diaz noted, it did not have a significant proinflammatory effect or cause any excess adverse events.

Overall, adverse events were similar between the active and placebo groups including atrial fibrillation (none), major bleeding (none), minor bleeding (7 events vs 10 events), gastrointestinal symptoms (6.8% vs 7.0%), and diarrhea (8.6% vs 7.7%).

Although it missed the primary endpoint, Diaz said, "this is the first large, randomized blinded trial to demonstrate excellent safety and tolerability of an 8 gram per day loading dose of icosapent ethyl, opening up the potential for acute use in randomized trials of myocardial infarction, acute coronary syndromes, strokes, and revascularization."

During a discussion of the results, Diaz said the Delta variant was not present at the time of the analysis and that the second half of the trial will report on whether icosapent ethyl can reduce the risk for hospitalization or death in participants diagnosed with COVID-19.

ECLA PHRI COLCOVID was supported by the Estudios Clínicos Latino América Population Health Research Institute. PREPARE-IT was supported by Estudios Clínicos Latino América with collaboration from Amarin. Diaz reports no relevant financial relationships.

European Society of Cardiology Congress 2021. Presented August 29, 2021.

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