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Treatment with the antiviral remdesivir (Veklury) plus dexamethasone was linked to fewer deaths among patients hospitalized for COVID-19 compared with dexamethasone monotherapy, a retrospective study suggested.

Using propensity score matching, the drug duo was associated with an overall 26% reduction in mortality at 14 days (adjusted HR 0.74, 95% CI 0.69-0.78, P<0.0001) and an overall 24% reduction at 28 days (aHR 0.76, 95% CI 0.72-0.81, P<0.0001) when compared with dexamethasone alone, reported Andre Kalil, MD, MPH, of the University of Nebraska Medical Center in Omaha, and colleagues in .

Of note, remdesivir plus dexamethasone was tied to a decreased risk of mortality at 14 days across all baseline oxygen requirements, when compared with dexamethasone monotherapy:

• No supplemental oxygen: aHR 0.79 (95% CI 0.72-0.87, P<0.0001)
• Low-flow oxygen: aHR 0.70 (95% CI 0.64-0.77, P<0.0001)
• High-flow oxygen/noninvasive ventilation: aHR 0.69 (95% CI 0.62-0.76, P<0.0001)
• Invasive mechanical ventilation/extracorporeal membrane oxygen (IMV/ECMO): aHR 0.78 (95% CI 0.64-0.94, P=0.0102)

These reductions in mortality risk were similar at 28 days.

The observed lower mortality with remdesivir plus dexamethasone in patients on IMV/ECMO "further supports the growing evidence that viral replication may persist late in the course of the disease even in patients who require IMV/ECMO and are not immunocompromised," Kalil and investigators wrote.

However, in an , Todd Lee, MD, MPH, of McGill University Health Centre in Montreal, noted that the study design raises numerous questions.

"One elephant in the room" was that more than 40% of patients in the study who received dexamethasone were apparently not on supplemental oxygen, he pointed out. Dexamethasone is for these patients because it is linked to a higher mortality rate. "It becomes challenging to know what to make of this population," he wrote.

Other findings in the study "may overstate the benefit of remdesivir," he added, because the study excluded people who were discharged within 2 days of admission (i.e., likely untreated), critically ill patients who received the Janus kinase inhibitor baricitinib (Olumiant) or the interleukin-6 inhibitor tocilizumab (Actemra), and those who died within the first 2 days of admission.

The researchers also excluded patients who received remdesivir later than 2 days after admission. "So, patients whose illness progressed from baseline would only be included if they continued to receive dexamethasone monotherapy despite deterioration," Lee wrote. "Why would the doctors not start remdesivir in a COVID-19 patient who was getting worse?"

"We will never truly know why some patients received remdesivir and some did not," he noted.

"If patients who are initially not on oxygen deteriorate, neither the [randomized controlled trials] nor this paper tell us whether adding remdesivir improves outcomes at that point, but it seems like a very reasonable approach," Lee continued. "Whether remdesivir has mortality benefit in patients on IMV/ECMO remains unclear," and it is now recommended that those patients should receive and dexamethasone, not remdesivir.

Baricitinib and tocilizumab were not the standard of care for the treatment of severe COVID-19 with hypoxemia when earlier randomized controlled trials looked at remdesivir efficacy.

In patients without hypoxemia, remdesivir may reduce illness duration and mortality, but the benefit may be too small to be cost-effective in a population with substantial vaccine-induced and natural immunity, Lee said.

The evolving state of evidence for COVID-19 therapeutics "is like an unlabeled milk carton in the refrigerator: without knowing the expiry date, it can be hard to know whether to drink it," he concluded. "In these cases, we need to use judgment, prior knowledge, and our noses."

The study, which looked at data from December 2021 to April 2023, included 33,037 patients with a primary discharge diagnosis of COVID-19 who received remdesivir plus dexamethasone or dexamethasone only during hospitalization. Most patients were 65 years of age or older (72%) and white (78%).

At baseline, 45% of patients did not receive any supplemental oxygen, 37% received low-flow oxygen, 16% received high-flow oxygen/noninvasive ventilation, and 3% received IMV/ECMO. Mortality rates according to baseline oxygen requirements at 14 and 28 days were:

• No supplemental oxygen: 5.6% and 7.2% with remdesivir plus dexamethasone vs 6.1% and 7.7% with dexamethasone alone
• Low-flow oxygen: 6.1% and 8.1% vs 7.7% and 9.7%
• High-flow oxygen/noninvasive ventilation: 12.7% and 17.6% vs 15.7% and 20.7%
• IMV/ECMO: 23.5% and 32.7% vs 27.1% and 35.4%

The study excluded patients who received other COVID-19 treatments, including other antiviral medications. Exclusion criteria included pregnancy, incomplete data, discharge or death within the first 2 days of admission, and transfer from hospice or another hospital, among others.

Note: On September 20, Gilead announced a of one lot of remdesivir 100 mg/vial (#47035CFA) due to a consumer complaint of a glass particle in the vial.

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