BACKGROUND: Many recent studies have investigated the role of drug interventions 
for coronavirus disease 2019 (COVID-19) infection. However, an important 
question has been raised about how to select the effective and secure 
medications for COVID-19 patients. The aim of this analysis was to assess the 
efficacy and safety of the various medications available for severe and 
non-severe COVID-19 patients based on randomized placebo-controlled trials 
(RPCTs).
METHODS: We did an updated network meta-analysis. We searched the databases from 
inception until July 31, 2021, with no language restrictions. We included RPCTs 
comparing 49 medications and placebo in the treatment of severe and non-severe 
patients (aged 18 years or older) with COVID-19 infection. We extracted data on 
the trial and patient characteristics, and the following primary outcomes: 
all-cause mortality, the ratios of virological cure, and treatment-emergent 
adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used 
as effect estimates.
RESULTS: From 3,869 publications, we included 61 articles related to 73 RPCTs 
(57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), 
comprising 20,680 patients. The mean sample size was 160 (interquartile range 
96-393) in this study. The median duration of follow-up drugs intervention was 
28 days (interquartile range 21-30). For increase in virological cure, we only 
found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% 
CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed 
to be associated with non-severe COVID-19 patients when compared with placebo, 
in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 
5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that 
proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), 
and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with 
non-severe COVID-19 patients; however, we only found that immunoglobulin gamma 
(OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when 
compared with placebo. For change in treatment-emergent adverse events, we only 
found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe 
COVID-19 patients; however, we did not find any medications that presented a 
statistical difference when compared with placebo among severe COVID-19 
patients.
CONCLUSION: We conclude that marked variations exist in the efficacy and safety 
of medications between severe and non-severe patients with COVID-19. It seems 
that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, 
imatinib, and sotrovimab) are a better choice for treating severe or non-severe 
COVID-19 patients. Clinical decisions to use preferentially medications should 
carefully consider the risk-benefit profile based on efficacy and safety of all 
active interventions in patients with COVID-19 at different levels of infection.