IMPORTANCEWidely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization. OBJECTIVE To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19. DATA SOURCES World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. STUDY SELECTION Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included. DATA EXTRACTION AND SYNTHESISThe PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool and a bayesian random effects meta-analysis with different estimates of prior probability was conducted: a weakly neutral prior (50% chance of efficacy with 95% CI for risk ratio [RR] between 0.5 and 2.0) and a moderately optimistic prior (85% chance of efficacy). A frequentist random-effects metaanalysis was conducted as a senstivity analysis, and the results were contextualized by estimating the probability of any association (RR Յ 1) and moderate association (RR Յ 0.9) with reduced hospitalization. MAIN OUTCOMES AND MEASURES All-cause hospitalization. RESULTSThis systematic review and meta-analysis of 3 randomized clinical trials and included 2196 participants. The RRs for hospitalization were 0.78 (95% CI, 0.58-1.08) for the bayesian weakly neutral prior, 0.73 (95% CI, 0.53-1.01) for the bayesian moderately optimistic prior, and 0.75 (95% CI, 0.58-0.97) for the frequentist analysis. Depending on the scenario, the probability of any association with reduced hospitalization ranged from 94.1% to 98.6%, and the probability of moderate association ranged from 81.6% to 91.8%. CONCLUSIONS AND RELEVANCEIn this systematic review and meta-analysis of data from 3 trials, under a variety of assumptions, fluvoxamine showed a high probability of being associated with reduced hospitalization in outpatients with COVID-19. Ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates. Meanwhile, fluvoxamine could be recommended as a management (continued)
Importance: Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly therapies that prevent hospitalization. Objective: Perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19. Data Sources: World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Study Selection: Completed outpatient trials with available results which compared fluvoxamine to placebo. Data Extraction and Synthesis: We followed the PRISMA 2020 guidelines. We extracted study details in terms of inclusion criteria, trial demographics and the pre-specified outcome of all-cause hospitalization. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool. We conducted a frequentist random effects meta-analysis, as well as two sensitivity analyses using a Bayesian random effects meta-analysis with different estimates of prior probability: a weakly neutral prior (50% chance of efficacy with 95% confidence interval for Risk Ratio [RR] between 0.5 and 2) and a moderately optimistic prior (85% chance of efficacy). We contextualized the results by estimating the probability of any effect (RR ≤1) and moderate effect (RR ≤0.9) on reducing hospitalization. Main Outcome(s) and Measure(s): All cause hospitalization. Results: 2196 participants were included from 3 identified trials. The risk ratios for hospitalization were 0.75 (95%CI, 0.57-0.97) for the frequentist analysis, 0.78 (95%CI 0.58-1.08) for the Bayesian weakly neutral prior, and 0.73 (95%CI, 0.53-1.01) for the Bayesian moderately optimistic prior. Depending on the scenario, the probability of any effect on hospitalization ranged from 94.1% to 98.3% and a moderate effect from 81.6% to 91.1%. Conclusions and Relevance: Under a variety of assumptions, fluvoxamine shows a high probability of preventing hospitalization in outpatients with COVID-19. While ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates, fluvoxamine could be recommended as a treatment option, particularly in resource-limited settings or persons without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals.
ImportanceDespite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when given to outpatients. Several large investigator-initiated randomized clinical trials have not yet been meta-analyzed.ObjectiveTo assess the efficacy and safety of oseltamivir in preventing hospitalization among influenza-infected adult and adolescent outpatients.Data SourcesPubMed, Ovid MEDLINE, Embase, Europe PubMed Central, Web of Science, Cochrane Central, ClinicalTrials.gov, and WHO International Clinical Trials Registry were searched from inception to January 4, 2022.Study SelectionIncluded studies were randomized clinical trials comparing oseltamivir vs placebo or nonactive controls in outpatients with confirmed influenza infection.Data Extraction and SynthesisIn this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two independent reviewers (R.H. and É.B.C.) extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 2.0. Each effect size was pooled using a restricted maximum likelihood random effects model. The quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.Main Outcomes and MeasuresHospitalization was pooled as risk ratio (RR) and risk difference (RD) estimates with 95% CIs.ResultsOf 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6295 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.6% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population (RR, 0.77; 95% CI, 0.47-1.27; RD, −0.14%; 95% CI, −0.32% to 0.16%). Oseltamivir was also not associated with reduced hospitalization in older populations (mean age ≥65 years: RR, 0.99; 95% CI, 0.19-5.13) or in patients considered at greater risk of hospitalization (RR, 0.90; 95% CI, 0.37-2.17). Within the safety population, oseltamivir was associated with increased nausea (RR, 1.43; 95% CI, 1.13-1.82) and vomiting (RR, 1.83; 95% CI, 1.28-2.63) but not serious adverse events (RR, 0.71; 95% CI, 0.46-1.08).Conclusions and RelevanceIn this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.
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