Reference: JAMA. 2020 Sep 15;324(11):1048-1057
In May this year, the FDA authorized emergency use of remdesivir in hospitalized patients with severe COVID-19. The authorization occurred after publication of the ACTT-1 trial, which was reviewed in an EBM Focus earlier this year. The ACTT-1 study population was fairly sick: about 25% were intubated or on extracorporeal membrane oxygenation (ECMO), and 90% required oxygen. Data from those 1,059 patients indicated a shorter time to recovery with remdesivir (11 vs. 15 days) but no significant difference in mortality; however, the possibility of benefit could not be excluded. A subsequent NIH guideline on treatment of COVID-19 recommended 10 days of remdesivir in patients requiring high-flow oxygen, BiPAP, mechanical ventilation, or ECMO, with 5 days for all other patients on supplemental oxygen. In late August, an open-label trial sponsored by Gilead was published in JAMA evaluating remdesivir for hospitalized patients less ill than those in the ACTT-1 trial. This trial was followed by an expanded FDA authorization in August 2020 of remdesivir for any patient hospitalized with COVID.
In this most recent trial, 596 patients aged ≥ 12 years (median age 57 years, 61% male) hospitalized with laboratory-confirmed COVID-19 and moderate pneumonia (pulmonary infiltrates and room air oxygen saturation > 94%) were randomized to one of three groups: standard care alone, or standard care plus either 5 or 10 days of remdesivir (200 mg IV on day 1 followed by 100 mg IV daily for either 4 or 9 days). Outcomes were evaluated on a 7-point ordinal scale of morbidity where death was 1 and discharge was 7, with improvement defined as an increase of at least 2 points on this 7-point scale. Median length of treatment was 5 days in the 5-day remdesivir group and 6 days in the 10-day remdesivir group. At day 11, at least 2 points of improvement were observed in 65% of the 10-day remdesivir group, 70% of the 5-day remdesivir group, and 61% of the standard-care-only group. The only significant difference was between 5 days of remdesivir and standard care alone. There were no significant differences in mortality, time to recovery, duration of oxygen therapy, or length of hospitalization amongst the three groups.
This trial suggests remdesivir may help patients improve a little faster, consistent with the ACTT-1 trial. There are, however, numerous concerns with the data. First, seeing benefit in the 5-day but not the 10-day remdesevir group seems peculiar, and raises the possibility that this is a chance finding. It could also suggest that there is some harm associated with prolonged treatment, but that seems less likely given that the median duration of treatment in the 10-day group was only 6 days. Second, since the scale used is ordinal and not cardinal, improving by two points means different things depending on where on the scale you start. For example, getting off a ventilator is more meaningful than decreasing the level of oxygen support, so an outcome capturing the percent of patients who are improving by two points may miss subtle differences in the group. Third, the dichotomous outcome reporting treats patients who worsened and those who do not get better as one group. Finally, the lack of benefit for any specific outcome such as mortality or length of hospital stay supports the impression that while remdesivir may have a benefit, it is a modest one at best. This skepticism is reflected in the IDSA’s recommendation for 5 days of remdesevir only in hospitalized patients sick enough to require supplemental oxygen, with longer use reserved for those on mechanical ventilation or ECMO.
For more information, see the topic COVID-19 (Novel Coronavirus) in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School. Edited by Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed, and Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed.