COVID-19 research briefs: BMJ living systematic review of drugs for treatment; 5 days equivalent to 10 days of remdesivir

Reference

Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ 2020;370:m2980.

Synopsis

Synopsis: Research Brief #53: This team performed a high-quality systematic review of randomized trials of treatments for people with suspected, probable, or confirmed COVID-19. Their review process included searching for studies from more than 31 databases and preprint servers every day and assessing the risk of bias of the included studies. The team extracted all kinds of data, including study characteristics (eg, publication status, study status, design features, and so forth), patient demographics, smoking habits, comorbidities, setting and type of care, COVID severity, and outcomes. The outcomes included a spectrum of less-patient-relevant events, such as time to viral clearing, to more clinically important ones, like mechanical ventilation and death. In addition to the systematic review, the authors pooled data and performed network meta-analyses for the various outcomes. Their process identified 13 published trials (2568 persons), 10 preprints (7167 persons), and 9 more (6156 persons) "upcoming" trials. All but 2 studies were at "probably high" or "high" risk of bias. In other words, the data that exist are of questionable reliability and there are a lot more data that have yet to be peer-reviewed. This is a true work in progress. The BMJ online version of the paper includes a really nice interactive feature that allows you to quickly see summary data and conclusions for each of the 8 individual outcomes, a few of which are summarized. In 15 trials (8654 persons), only glucocorticoids were likely to reduce mortality compared with standard care (37 fewer deaths per 1000 persons). In 8 trials (6953 participants), only glucocorticoids were likely to reduce the need for mechanical ventilation (30 fewer per 1000 persons). In the 11 trials (1875 participants) that reported adverse events, the authors found that remdesivir decreased the duration of symptoms and did not cause any additional harm compared with standard care, and that hydroxychloroquine increased the risk of adverse events. It appears that more data are out there, and fortunately, the authors plan to revisit the data frequently. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ 2020;370:m2980. doi: https://doi.org/10.1136/bmj.m2980 Research Brief #54: We have previously summarized several studies of remdesivir published in NEJM. A Research Brief posted on April 17 described a case series with 53 patients with severe COVID-19. The ACTT study that we reported in a Research Brief posted on April 30 (then updated in a Research Brief on June 2) was a randomized trial of 1063 patients with COVID-19 with lung involvement that found speedier recovery and a trend toward lower mortality with remdesivir. In contrast, a Chinese randomized trial with 237 patients with COVID-19 pneumonia and hypoxia found no improvement in mortality with remdesivir. We also summarized a flawed study (Research Brief on June 3) that found comparable outcomes of 5 days and 10 days of remdesivir in patients with severe COVID-19. Finally, a recent systematic review in BMJ (see above) found that remdesivir had no overall benefit on mortality, the use of mechanical ventilation, duration of mechanical ventilation, viral clearance, or hospital length of stay, but it decreased symptom duration and was unlikely to cause adverse events. We now have another randomized trial, from the same team that compared 5 days and 10 days in patients with severe COVID-19, which was not included in the aforementioned systematic review. The researchers randomized patients who were hospitalized with moderate COVID-19 pneumonia (not requiring mechanical ventilation, no acute respiratory distress syndrome) to receive, unmasked, 10 days of remdesivir (n = 197), 5 days of remdesivir (n = 199), or usual care (n=200). This study used a 7-point scale (ranging from death to hospitalized with various measures to not hospitalized) and had significant differences in baseline characteristics of the patients. For example, the patients randomized to receive 10 days of remdesivir were slightly more likely to have diabetes (44% vs 37% and 38%) and approximately 10% of patients randomized to receive either remdesivir arm also received hydroxychloroquine compared with nearly half of the patients who received usual care. Regardless, the authors report that after 11 days, compared with those who received usual care, the distribution of clinical status based on the 7-point scale was significantly better statistically for those who received 5 days of remdesivir but no different for those who received 10 days of remdesivir. This oddity might be explained by serious remdesivir toxicity that accrues after 5 days or by inadequate accounting for baseline differences. It may also be purely a random finding. There may be other explanations, but this finding suggests that better studies are needed. The authors reasonably question if the difference is clinically important. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 2020;324(11):1048-1057. doi: https://doi.org/10.1001/jama.2020.16349