Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients With Influenza

Abstract

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.

Oseltamivir May or May Not Reduce Hospitalizations

“…Although a meta-analysis of pooled data from underpowered RCTs increases precision, given the very low hospitalization rate (0.6%) among the untreated control population, the total number of participants was still substantially underpowered to assess the benefit of oseltamivir treatment in averting hospitalization. Therefore, the study’s findings were inconclusive.…”

“…To clarify whether oseltamivir treatment of outpatients with seasonal influenza reduces the risk of severe disease requiring hospitalization, a sufficiently powered RCT of early oseltamivir treatment vs placebo is needed among outpatients with laboratory-confirmed influenza and increased risk of influenza complications (eg, adults with certain comorbidities, pregnant people, persons aged ≥65 years) . As the authors noted, depending on the expected hospitalization rate, a sufficiently powered RCT would require a minimum of 15 000 to 30 000 participants; ie, more than 2 to 4 times the number of participants included in their meta-analysis.…”

Oseltamivir May or May Not Reduce Hospitalizations

“…The meta-analysis itself was underpowered to detect an association between oseltamivir and hospitalization . The study compared 3443 oseltamivir-exposed patients vs 2852 unexposed and reported a relative risk (RR) of hospitalization of 0.77 (95% CI, 0.47-1.27).…”

Corrections to a Meta-Analysis of Oseltamivir Use in Preventing Hospitalization for Influenza

“…To the Editor On behalf of my coauthors and myself, I write to explain the correction of our Original Investigation, “Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients With Influenza: A Systematic Review and Meta-Analysis,” published online first on June 12, 2023, in JAMA Internal Medicine . This systematic review and meta-analysis included data from 15 randomized clinical trials and accurately concluded that oseltamivir was not associated with reduced risk of first hospitalization compared with placebo or standard of care.…”

“…However, when we received a request to share our study data, we realized that a number of inadvertent transcription and transposition errors had occurred in our response to peer review. These errors were primarily introduced by migrating back and forth between the intention-to-treat and intention-to-treat infected populations for the requested sensitivity analyses; “no hospitalization” and “total population” being transposed in a spreadsheet; and use of different parameters in creating forest plots with the counts as “yes/no” in the latter version vs “yes/total” during drafting.…”