Tools for Practice


#131: Anti-virals for Flu: Looking for evidence for “Stockpile, store, expire, repeat”


CLINICAL QUESTION
Do neuramidase inhibitors (NIs) oseltamivir (Tamiflu®) and/or zanamivir (Relenza®) improve clinical outcomes in healthy patients with influenza or influenza-like illness?


BOTTOM LINE
Biased, poor quality, mostly unpublished evidence demonstrates that oseltamivir and zanamivir shorten the duration of influenza symptoms by ~1/2 a dayObjectively defined pneumonia or hospitalizations are not decreased.  



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EVIDENCE
2014 systematic reviews (three publicationsof randomized, placebo-controlled trials (RCTs) including >160,000 pages of previously unreleased clinical study reports.1-3 
  • Treating influenza-like illness or influenza in primarily healthy adults, oseltamivir (11 RCTs)1,2 and zanamivir (14 RCTs):1,3 
    • Time to symptom improvement 0.6-0.7 days (~10%) better.1-3 
      • Zanamivir benefit similar to “relief medications” (like acetaminophen/paracetamol).1,3 
    • Pneumonia (x-ray confirmed)No benefit.1-3  
    • Hospitalizations: No benefit1,2 or not reported.1,3 
    • Adverse events:  
      • Oseltamivir:1,2  
        • Number Need to Harm: Nausea=28vomiting=22.  
      • Post-marketing surveillance reports (frequency unknown)  
        • ZanamivirBronchospasm.4 
        • OseltamivirDelirium and self-injury.5  
2015 systematic review6 concluded adults receiving oseltamivir had faster symptom alleviation, fewer lower respiratory tract complications and hospitalizations. 
  • Used similar studies1,2 but conclusion based on subgroup of documented influenza. 
  • Review funded by, and two authors had pre-existing industry financial affiliations, with manufacturer of oseltamivir. 
From 26 systematic reviews, authors with financial conflicts of interest were:7 
  • Five times more likely to report benefits of NI use. 
    • This includes a systematic review of cohort studies from the 2009-10 pandemic suggesting that NIs decrease mortality in hospitalized patients.8 
  • Less likely to report on publication bias and quality of included studies. 
Other concerns (beyond publication bias):1 Not publishing protocols; inconsistent outcome definition; using “placebos” with potential adverse effects; incomplete reporting (example missing symptom cards).  Context:   
  • Since 1999, oseltamivir sales are >$18 billion, half from governments and companstockpiling. Most have never been used.9 
  • NIs: Not recommended if symptoms >48 hours.4,5  
    • Zanamivir: Contraindicated: Asthma or COPD.4 
    • Oseltamivir: Limited evidence: underlying cardiac or respiratory disease.5 
  • Limited data suggests NIs likely safe in pregnancy10 although makers of: 
    • Zanamivir dont recommend in pregnancy.4  
    • Oseltamivir conclude insufficient data; only use when potential benefit justifies potential risk to fetus.5 


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Author(s):

  • Christina Korownyk MD CCFP
  • Michael Kolber BSc MD CCFP MSc

1. Jefferson T, Jones MA, Doshi P, et al. Cochrane Database Syst Rev. 2014 Apr 10; 4:CD008965.

2. Jefferson T, Jones MA, Doshi P, et al. BMJ. 2014; 348:g2545.

3. Heneghan CJ, Onakpoya I, Thompson M, et al. BMJ. 2014; 348:g2547.

4. Relenza® (product monograph on the internet). Mississauga, ON: GlaxoSmithKline Inc., 2012. Available from: http://www.gsk.ca/english/docs-pdf/product-monographs/Relenza.pdf Accessed December 17, 2014.

5. Tamiflu® (product monograph on the internet). Mississauga, ON: Hoffmann-La Roche Limited, 2014. Available from: http://www.rochecanada.com/fmfiles/re7234008/Research/ClinicalTrialsForms/Products/ConsumerInformation/MonographsandPublicAdvisories/Tamiflu/Tamiflu_PM_E.pdf Accessed December 17, 2014.

6. Dobson J, Whitley RJ, Pocock S, Monto AS. Lancet 2015 (published online January 30, 2015). Available at: http://dx.doi.org/10.1016/ S0140-6736(14)62449-1.

7. Dunn AG, Arachi D, Hudgins J, et al. Ann Intern Med. 2014; 161:513-8.

8. Muthuri SG, Venkatesan S, Myles PR, et al. Lancet Respir Med. 2014 May; 2(5):395-404.

9. Jack A. BMJ. 2014; 348:g2524.

10. Dunstan HJ, Mill AC, Stephens S, et al. BJOG. 2014; 121:901-6.

Authors do not have any conflicts to disclose.