COVID-19 patients already on ventilators don't benefit from remdesivir, but the antiviral drug offers a slight reduction in death or progression to ventilation among other hospitalized patients, according to final results from the adaptive World Health Organization's (WHO's) Solidarity randomized trial and an updated meta-analysis.
The findings, published this week in The Lancet, were from an ongoing study of four repurposed antiviral drugs as treatments for COVID-19 in hospitalized patients. The researchers had previously stopped studying the drugs lopinavir, hydroxychloroquine, and interferon β1a because they showed no benefits. Enrollment in the remdesivir arm, however, continued until donated supplies ran low.
The trial enrolled 14,221 patients from 454 hospitals in 35 countries in six WHO regions, including 8,275 randomly assigned to receive either up to 10 daily infusions of remdesivir or an open-label control drug from Mar 22, 2020, to Jan 29, 2021, before the emergence of the Delta and Omicron variants.
No benefit for patients already on ventilators
A total of 602 of 4,146 (14.5%) patients assigned to remdesivir died, compared with 643 of 4,129 (15.6%) control patients (mortality rate ratio [RR], 0.91; 95% confidence interval [CI], 0.82 to 1.02).
Among the 359 patients already on a ventilator, 151 (42.1%) assigned to remdesivir died, compared with 134 of 347 (38.6%) control patients (RR, 1.13; 95% CI, 0.89 to 1.42).
Of patients not on a ventilator but receiving high- or low-flow oxygen, 14.6% of remdesivir recipients and 16.3% of controls died (RR, 0.87; 95% CI, 0.76 to 0.99). Among the 1,730 patients who didn't need oxygen at hospital admission, 2.9% of remdesivir participants and 3.8% of controls died (RR, 0.76; 95% CI, 0.46 to 1.28).
When all patients not initially requiring ventilation were combined, 11.9% of remdesivir recipients and 13.5% of controls died (RR, 0.86; 95% CI, 0.76 to 0.98), and 14.1% and 15.7%, respectively, progressed to need ventilation (RR, 0.88; 95% CI, 0.77 to 1.00). The composite outcome of death or progression to ventilation occurred in 19.6% of remdesivir recipients, compared with 22.5% of controls (RR, 0.84; 95% CI, 0.75 to 0.93].
The meta-analysis of all randomized trials of remdesivir versus no remdesivir that had death data available had comparable findings.
The trial and meta-analysis suggest that remdesivir didn't reduce the death rate in already-ventilated patients but conferred a slight benefit to patients receiving oxygen but not ventilation, the authors noted. "However, given that high-flow and low-flow oxygen were not recorded separately at enrollment into Solidarity, it is not known whether any protective effect in non-ventilated patients extends to those on high-flow oxygen," they wrote.
Better COVID treatments still needed
The findings aren't materially different from those of interim results published in February 2021 in the New England Journal of Medicine, the researchers said. "This additional evidence has, however, reduced the statistical uncertainty in the mortality RRs," they wrote, adding that the final results also produced more solid evidence on progression to ventilation among remdesivir recipients.
But regardless of these findings, better drugs to treat COVID-19 will still be needed, the researchers said. "Oral antiviral agents, various immune modulators, and monoclonal antibodies against currently circulating variants of concern are now emerging that might prove more effective, more convenient, or less expensive than daily remdesivir infusions, but large-scale randomised evidence will be needed to evaluate and compare them," they wrote.
In a commentary in the same journal, Carolina Garcia-Vidal, MD, PhD, of the University of Barcelona in Spain, and Maurizio Sanguinetti, MD, of the Fondazione Policlinico Universitario A Gemelli IRCCS in Rome, said that the conclusions of the study were limited by not including data on days from illness onset to remdesivir administration, viral loads measured by cycle threshold values, viral antigen levels, and other factors.
Also, more recent events in the course of the pandemic, including the emergence of Delta and Omicron and the wide availability of COVID-19 vaccination, may limit the findings applicability to today's situation. "Debate about when and which patients should receive remdesivir or co-adjuvant treatments will, therefore, continue," they wrote.
"Still, the research conducted by the WHO Solidarity Trial Consortium adds meaningfully to the evidence base by demonstrating that we now know remdesivir can reduce the risk of death or progression of mechanical ventilation (or both) in hospitalised patients with COVID-19 requiring oxygen therapy," Garcia-Vidal and Sanguinetti wrote.