TY - JOUR
T1 - Drug interventions for prevention of COVID-19 progression to severe disease in outpatients
T2 - a systematic review with meta-analyses and trial sequential analyses (The LIVING Project)
AU - Petersen, Johanne Juul
AU - Jørgensen, Caroline Kamp
AU - Faltermeier, Pascal
AU - Siddiqui, Faiza
AU - Feinberg, Joshua
AU - Nielsen, Emil Eik
AU - Torp Kristensen, Andreas
AU - Juul, Sophie
AU - Holgersson, Johan
AU - Nielsen, Niklas
AU - Bentzer, Peter
AU - Thabane, Lehana
AU - Kwasi Korang, Steven
AU - Klingenberg, Sarah
AU - Gluud, Christian
AU - Jakobsen, Janus C
N1 - © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023/6/20
Y1 - 2023/6/20
N2 - OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients.SETTING: Outpatient treatment.PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities.INTERVENTIONS: Drug interventions authorised by EMA or FDA.PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events.RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups.CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression.PROSPERO REGISTRATION NUMBER: CRD42020178787.
AB - OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients.SETTING: Outpatient treatment.PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities.INTERVENTIONS: Drug interventions authorised by EMA or FDA.PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events.RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups.CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression.PROSPERO REGISTRATION NUMBER: CRD42020178787.
KW - COVID-19
KW - epidemiology
KW - general medicine (see internal medicine)
KW - primary care
KW - public health
KW - quality in health care
UR - http://www.scopus.com/inward/record.url?scp=85163921350&partnerID=8YFLogxK
U2 - 10.1136/bmjopen-2022-064498
DO - 10.1136/bmjopen-2022-064498
M3 - Review
C2 - 37339844
SN - 2399-9772
VL - 13
JO - BMJ Paediatrics Open
JF - BMJ Paediatrics Open
IS - 6
M1 - e064498
ER -