Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Johanne Juul Petersen, Caroline Kamp Jørgensen, Pascal Faltermeier, Faiza Siddiqui, Joshua Feinberg, Emil Eik Nielsen, Andreas Torp Kristensen, Sophie Juul, Johan Holgersson, Niklas Nielsen, Peter Bentzer, Lehana Thabane, Steven Kwasi Korang, Sarah Klingenberg, Christian Gluud, Janus C. Jakobsen

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish
Article numbere064498
JournalBMJ Open
Volume13
Issue number6
DOIs
Publication statusPublished - 2023 Jun

Subject classification (UKÄ)

  • Cardiac and Cardiovascular Systems

Free keywords

  • COVID-19
  • epidemiology
  • general medicine (see internal medicine)
  • primary care
  • public health
  • quality in health care

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