Date: July 6, 2023

Reference: Hanula R et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and meta-analysis. JAMA Int Med 2023.

Guest Skeptic: Dr. Anand Swaminathan is an Assistant Professor of Emergency Medicine at Staten Island University Hospital. Managing editor of EM:RAP and Associate Editor at REBEL EM.

Case: A 57-year-old woman with hypertension, hyperlipidemia and type-2 diabetes mellitus presents to the emergency department (ED) with fever, cough, myalgias, headache and congestion. It’s flu season and you’ve already seen 15 people with the same symptoms. Her vitals look good: Temperature 38.5C, heart rate 102 beats/minute, blood pressure 143/88 and oxygen saturation of 99% on room air.  She is breathing comfortably without any increased work of breathing. You send off COVID and flu swabs and the results come back as positive for influenza. She looks well enough to go home but asks if she should be prescribed oseltamivir (Tamiflu) because some of her friends have been given it recently by their doctors.

Background: Oseltamivir was approved by the FDA in 1999 based on evidence from trials funded by the maker of the drug, Roche. Safety issues popped up soon after widespread use of the drug including neuropsychiatric effects as well as the more common adverse effects of nausea and vomiting.

The Cochrane collaboration published analyses of the available data in 1999, 2003 and 2006. In 2009, the Cochrane group questioned Roche about the completeness of the data and after four years of requests, finally got access to all the data in 2013 and updated their review in 2014. We covered this SRMA on SGEM#98.

The 2014 Cochrane review found an improvement in time to first alleviation of symptoms in adults by about 17 hours coupled with several side effects including nausea, vomiting, headaches, and neuropsychiatric effects.

Despite these findings, the World Health Organization (WHO), Infection Disease Society of America (IDSA) and the Center for Disease Control and Prevention (CDC) all continue to recommend use of oseltamivir, particularly in patients at increased risk of hospitalization and bad outcomes.

There was a large unblinded RCT of over 3,000 patients published in the Lancet in 2020. It looked at patients presenting to their primary care physician with influenza. The results were those treated with oseltamivir recovered about one day earlier than the control group but experienced more nausea and vomiting. This was critically appraised on SGEM#312.

A subgroup analysis of the Lancet RCT showed that older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner. While this is interesting it should be considered hypothesis generating. Wallach et al JAMA Intern Med 2017, previously reported that subgroup claims are often not corroborated by subsequent studies and rarely confirmed. Also, Yusuf et al JAMA 1991 stated: “the overall trial result is usually a better guide to the direction of effect in subgroups than the apparent effect observed within a subgroup.”

When it comes to children suspected of influenza and ill enough to be admitted to hospital there was an observational study looking at the impact of oseltamivir (JAMA Ped 2022). SGEM Peds expert Dr. Dennis Ren did a structed critical appraisal of that study on SGEM#397. The bottom line from that episode was we do not have high-quality evidence to support the routine use of oseltamivir in the treatment of children admitted to hospital with suspected influenza.

Clinical Question: Is oseltamivir effective in preventing hospitalization from influenza in adults and adolescent outpatients?

Reference: Hanula R et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and meta-analysis. JAMA Int Med 2023.

  • Population: RCTs of outpatients 12 years and older diagnosed with natural influenza infections based on clinical history and laboratory evidence (PCR or 3x increase in antibody titers at 30 days).
    • Exclusions: Observational studies
  • Intervention: Oseltamivir 75 mg BID X 5 days
  • Comparison: Placebo or standard care
  • Outcome:
    • Primary Outcome: Hospitalization during the treatment or follow-up period for any cause or duration (Emergency department visits did not count).
    • Secondary Outcomes None
    • Safety Outcomes: Adverse events including nausea, vomiting, diarrhea, cardiac, psychiatric, neurologic or a composite of any gastrointestinaI symptoms

Authors’ Conclusions: “In 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.”

Quality Checklist for Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable.  Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. No
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. Yes
  7. The treatment effect was large enough and precise enough to be clinically significant. No
  8. Funding/Conflicts of Interest: Dr McDonald reported being an investigator in an inpatient oseltamivir study. No other disclosures were reported. Twelve of the included 15 RCTs were sponsored by a pharmaceutical company

Results: The search resulted in 15 RTCs being included in the review. Seven were peer reviewed published trials and eight unpublished clinical study reports (CSRs) from Roche Pharmaceuticals. The mean age was 45 years and 54% were female.

Key Result: No statistical difference in hospitalization

  • Primary Outcome: Hospitalization RR = 0.77 (95% CI; 0.47 to 1.27)
    • No statistical difference in older populations
    • No statistical difference in those at higher risk for hospitalization
  • Safety Outcomes:
    • Increase nausea RR 1.43 (95% CI; 1.13 to 1.82)
    • Increased vomiting RR 1.83 (95% CI; 1.28 to 2.63)
    • No statistical increase in serious adverse events

1. Age of Patients: The mean age of patients was 45 years. This probably represented a healthier cohort than an older population and less likely to be admitted to hospital with influenza. However, the subgroup analysis looking at older did not show an increased risk of hospitalization.

  • Hospitalization: Mean age ≥65 years: RR 0.99 (95% CI; 0.19 to 5.13)
  • Hospitalization: Mean age <65 years: RR 0.72 (95% CI; 0.39 to 1.34)

2. Higher-Risk Patients: While age generally represents a higher risk population, they did pre-specify another high-risk group based on co-morbidities. This too failed to show a statistical difference in hospitalization for this subgroup.

  • Hospitalization: High-risk: RR 0.90 (95% CI; 0.37 to 2.17)
  • Hospitalization: Low-risk: RR 0.63 (95% CI; 0.32 to 1.24)

3. Sponsored vs Non-Sponsored: Industry sponsored trials were showed less likely to be hospitalized. Authors give three possible explanations why sponsored trials were more likely to find a point estimate of no superiority in the treatment arm. This included using viral cultures instead of PCR to confirm infection and lower resistance when the industry funded studies were being conducted.

4. Publication Bias: Visual inspection of the funnel plot revealed asymmetry suggesting publication bias. However, the Egger test was not statistically significant (P = .66; eFigure 7 in Supplement 1).

5. GRADE: Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used in this SRMA. If found moderate-certainty evidence that oseltamivir had little to no effect on hospitalization. All included studies were RCTs directly evaluating oseltamivir, there was imprecision in the estimates due to wide variability between study results, not all studies were placebo- controlled, and some studies were at risk of bias.

So, while the certainty was moderate it was not in the direction favouring oseltamivir. Those making the claim that this treatment prevents hospitalization have the burden of proof to demonstrate their position. Without sufficient evidence we should accept the null hypothesis of no superiority. However, that is not claiming oseltamivir does not work. Then we would assume the burden of proof. It is possible that oseltamivir may work but we do not have high-quality evidence to support that position.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors about their interpretation of the data, but we don’t think an adequately powered trial in a suitably high-risk population is justified.

SGEM Bottom Line: Same as it ever was…we cannot recommend the routine use of oseltamivir to reduce the risk of hospitalization amongst outpatients diagnosed with influenza.

Case Resolution: You explain to your patient that the data tells us that she may have a slightly shorter course of influenza if she takes oseltamivir but that it won’t prevent the need for hospitalization. Additionally, it comes with an increased risk of nausea, vomiting and neuropsychiatric effects.

Based on this, the patient doesn’t feel like it would be advisable to take the drug. She agrees to schedule close follow up with her family physician and, in the meantime, order up some chicken soup.

Dr. Anand Swaminathan

Clinical Application: Despite the recommendations from WHO, CDC and IDSA, it seems the benefit of oseltamivir is minimal, and we don’t see a reason to make it a standard part of your treatment approach.

What Do I Tell My Patient? You have the flu. While there is a medication that may shorten your illness by less than one day it will not prevent you from being hospitalization and it comes with some unpleasant side effects like nausea, vomiting and will cost you about $20.

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