To the Editor
We read with great interest the work by Hanula and colleagues evaluating the association between oseltamivir and hospitalization.1 The authors performed a meta-analysis of 15 randomized clinical trials and concluded that “…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.”1 We consider a few caveats to be worth discussing.
It is unclear whether clinicians are prescribing oseltamivir mainly to prevent hospitalization. Early oseltamivir use decreases duration of symptoms, influenza-associated complications (eg, otitis and pneumonia), and antibiotic use.2 It is likely that the effects on these more proximal outcomes as emphasized in national guidelines are used to justify current practice.
The primary efficacy outcome of the meta-analysis was any cause hospitalization.1 However, this was not a primary efficacy end point in any of the included trials, and sometimes, not even a planned secondary end point. Measurements of nonprimary end points may be less precisely chosen, measured, analyzed, and even reported compared with primary end points. It is also unclear whether hospitalizations included in the meta-analyses were related to influenza or to oseltamivir, and the time frame for outcome assessment varied from 7 days postsymptom resolution to 28 days, adding to the potential imprecision.
The meta-analysis itself was underpowered to detect an association between oseltamivir and hospitalization.1 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). If the true RR for oseltamivir relative to untreated patients was 0.77, using the same ratio of oseltamivir exposed to unexposed and a control group hospitalization rate of 0.6%, a prospective trial would need approximately 48 704 patients who were oseltamivir exposed and 38 963 unexposed to reject the null hypothesis of RR = 1 (power = 0.8; α = .05).3 Given that oseltamivir is in the market and that generic formulations are also available, it is unlikely that a trial of this size will be conducted.
There is substantial underuse of influenza antivirals in children4 and adults.5 The conclusions stated by Hanula et al1 may be mistakenly interpreted as an indication that oseltamivir does not prevent hospitalization, despite that their meta-analysis was underpowered to assess the end point, one that the included studies were not designed to address. Whether oseltamivir prevents hospitalization remains unclear; however, prevention of hospitalization is not a key driver of oseltamivir use.
We recommend that clinicians use influenza antivirals as early as possible to limit duration of symptoms and specific influenza-associated complications. This recommendation is supported by existing clinical trials and professional societal guidelines.2
Conflict of Interest Disclosures:
Dr Antoon reported grants from the US National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases Career Development award (No. K23 AI168496) during the conduct of the study. Dr Grijalva reported serving on the advisory board of Merck and grants from NIH, the Agency for Healthcare Research and Quality, the US Centers for Disease Control and Prevention (CDC), and the US Food and Drug Administration outside the submitted work. Dr Talbot reported grants from the CDC during the conduct of the study.
Contributor Information
James W. Antoon, Division of Hospital Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Carlos G. Grijalva, Division of Pharmacoepidemiology, Departments of Health Policy and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Keipp Talbot, Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
References
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