Remdesivir Finally Shows Mortality Benefit in Hospitalized COVID Patients

Remdesivir (Veklury) reduced mortality in non-ventilated patients hospitalized with COVID-19, according to an individual patient data meta-analysis of nine randomized controlled trials (RCTs).

Among patients who received no oxygen or low-flow oxygen, 9.1% of those who were treated with remdesivir died within 28 days of randomization compared with 11.2% of those who did not receive the antiviral (adjusted OR 0.80, 95% CI 0.70-0.93), reported Benjamin Speich, PhD, of University Hospital Basel in Switzerland, and colleagues.

Of the patients on ventilation, including high-flow oxygen, 30% of remdesivir-treated patients died versus 28.5% of those not treated with remdesivir (aOR 1.10, 95% CI 0.88-1.38), they detailed in Lancet Respiratory Medicine and in a poster presentation at this year's Conference on Retroviruses and Opportunistic Infections.

"Although subgroup effects in RCTs need to be viewed critically, the consistent direction of effect modification across individual trials, statistical evidence (P_interaction=0.019 based on individual patient data), and previous evidence for a similar effect modification strengthened the credibility of this subgroup effect," the authors wrote.

Overall, 12.5% of those receiving remdesivir died within 28 days of randomization compared with 14.1% of those not receiving the antiviral (aOR 0.88, 95% CI 0.78-1.00, P=0.045), while at 60 days, the mortality rates were 13.7% versus 15.2%, respectively (P=0.116).

"The National Institutes of Health (NIH), the Infectious Diseases Society of America (IDSA), and WHO generally recommend remdesivir for patients hospitalized with mild to severe COVID-19," Speich and team wrote. "However, the National Institute for Health and Care Excellence (NICE) interprets the evidence differently and uncertainty remains, especially in terms of which subgroup of patients is most likely to benefit."

Of note, patients treated with remdesivir were less likely to need respiratory support, with a better clinical status than their counterparts at both 14 days (aOR 0.88, 95% CI 0.81-0.95, P=0.0015) and 28 days (aOR 0.87, 95% CI 0.80-0.96, P=0.0037).

In an invited commentary, Andre C. Kalil, MD, MPH, of the University of Nebraska Medical Center in Omaha, criticized the time it took to recommend the treatment for use in non-ventilated patients hospitalized for COVID.

"Prioritizing underpowered subgroup results instead of powered overall results helped to prevent the NIH and IDSA guidelines from recommending remdesivir to patients hospitalized for COVID-19 without supplemental oxygen for nearly 2 years, and prioritizing the interim results of a high risk of bias trial over the complete and beneficial results of a low risk of bias trial helped to prevent the WHO guidelines from recommending remdesivir to any patients for almost 3 years," Kalil wrote.

"How many more lives could have been saved had remdesivir been recommended more broadly and made more readily available? All of us -- the scientific community, public health agencies, professional societies, journal editors, and guideline committees -- must learn from these mistakes to provide more reliable scientific recommendations to directly benefit the individual care of patients globally, and to advocate for equitable access to safe and life-saving antiviral therapies such as remdesivir in low-income and middle-income countries," he concluded.

For this systematic review and meta-analysis, Speich and colleagues searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from January 2020 to April 11, 2022, for RCTs of remdesivir in adult patients hospitalized with COVID.

They included nine RCTs with a total of 10,480 patients. Median age was 58, 63.1% were men, and 58.1% had at least one comorbidity. Patients were randomly assigned after a median symptom duration of 9 days.

As for safety, 27.3% of patients receiving remdesivir experienced at least one grade 3 or 4 adverse event or serious adverse event within 28 days compared with 32.2% of patients who did not receive remdesivir.

One of the RCTs did not provide individual patient data, which was a limitation cited by Speich and co-authors. In addition, their data did not include patients with SARS-CoV-2 variants that were in widespread circulation only after April 2021, such as Delta, Omicron, and their sublineages, though they noted that remdesivir "maintains efficacy against emerging SARS-CoV-2 variants of concern, and has regained importance in clinical care owing to increasing resistance to current monoclonal antibodies."