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Review: Oseltamivir relieves symptoms but does not reduce hospitalizations in influenza FREE

Ann Intern Med. 2012;157(6):JC3-5. doi:10.7326/0003-4819-157-6-201209180-02005
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Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012;(1):CD008965. 22258996

Infectious Disease:

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Pulmonology:

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Questions: Are neuraminidase inhibitors effective for preventing or treating influenza in adults and children who are not immunocompromised? What are the harms?

Review scope: Included studies compared neuraminidase inhibitors with placebo or standard care as prophylaxis, postexposure prophylaxis, or treatment of naturally occurring influenza in previously healthy adults and children, including those with chronic illness, and had available unabridged clinical study report (CSR) modules. Exclusion criteria included illness affecting immune responses. Primary outcomes included symptom relief, hospitalization, complications, and harms.

Review methods: MEDLINE (from May 2009); EMBASE/Excerpta Medica (from Jan 2010); Cochrane Central Register of Controlled Trials, DARE, and NHSEED; US Food and Drug Administration, European Medicines Agency, UK National Institute for Health and Clinical Excellence, and Japanese Pharmaceutical and Medical Devices Agency documents; previous reviews and health technology assessments; trial registries; and drug product information sheets (all to 12 Apr 2011) were searched to identify published and unpublished randomized controlled trials (RCTs). Regulatory organizations and pharmaceutical companies were contacted for CSRs of RCTs and associated regulatory documents. 25 RCTs met inclusion criteria and had available CSRs: 15 evaluated oseltamivir (n = 9030 in 14 RCTs; mean age 5 to 82 y, and 41% to 69% women in 13 RCTs), and 10 evaluated zanamivir. Insufficient data were available or unresolved discrepancies existed for 42 additional RCTs. Meta-analyses were done for trials of oseltamivir; this abstract focuses on these results. 10 trials evaluated oseltamivir as treatment for influenza, 3 as prophylaxis, and 1 as postexposure prophylaxis; 1 evaluated safety. All included studies were sponsored by drug manufacturers; 11 trials of oseltamivir had adequate allocation concealment; 7 blinded participants, study personnel, and outcome assessors; and 14 had adequate outcome data for ≥ 1 outcome.

Main results: Meta-analysis showed that oseltamivir reduced time to first relief of influenza-like symptoms compared with placebo; groups did not differ for hospitalizations (Table). Oseltamivir increased nausea and vomiting but reduced diarrhea (Table). Data were insufficient to evaluate the effect of neuraminidase inhibitors on influenza complications.

Conclusion: In adults and children who are not immunocompromised, oseltamivir relieves influenza-like symptoms faster than placebo but does not reduce hospitalizations.

Oseltamivir vs placebo in nonimmunocompromised adults and children*

OutcomesNumber of trials (n)Weighted event ratesMean difference (95% CI)
Hours to first symptom relief5 (3713)−21 (−30 to −13)
RRR (CI)NNT (CI)
Hospitalization8 (4696)1.4% vs 1.5%5% (−59 to 43)Not significant
Diarrhea9 (5651)†5.2% vs 7.0%26% (3 to 44)55 (33 to 477)
RRI (CI)NNH (CI)
Nausea9 (5651)†8.5% vs 5.5%55% (15 to 109)34 (17 to 122)
Vomiting9 (5651)†7.9% vs 3.6%119% (57 to 204)24 (14 to 49)

*RRR, RRI, NNT, NNH, and CI calculated from data in article using a random-effects model. All RCTs were done in treatment settings unless otherwise indicated.

†Oseltamivir was used for postexposure prophylaxis in 1 RCT (n = 955).

Source of funding: National Institute of Health Research, UK.

For correspondence: Dr. T. Jefferson, The Cochrane Collaboration, Roma, Italy. E-mail jefferson.tom@gmail.com, jefferson@assr.it.


Neuraminidase inhibitors are widely used for preventing and treating influenza, although the net benefit to individual patients remains controversial. This systematic review by Jefferson and colleagues—updating previous versions dating from 1999—used a novel approach by obtaining documents and CSRs from regulatory authorities and from industry, thereby gaining access to both published and unpublished data. Whether such painstaking efforts provide more objective or precise treatment estimates remains to be seen.

Only 25 studies were included in the review; many were not included because insufficient information was obtained. The authors found modest benefits of neuraminidase inhibitors for relieving influenza symptoms but an increase in nausea and vomiting. Hospitalization rates were not reduced, but numbers were small and the wide confidence intervals do not rule out a clinically important reduction. Complications, such as pneumonia, could not be assessed due to trial program limitations.

An independent meta-analysis of 11 trials that examined complications found that oseltamivir reduced lower respiratory tract infections requiring antibiotics by 28% overall and by 37% in those with proven influenza (1). Similarly, a recent meta-analysis of observational studies found that neuraminidase inhibitors reduced all-cause mortality and hospitalization rates, although the quality of the evidence was low to very low (2).

Neuraminidase inhibitors in otherwise mainly healthy patients relieve influenza symptoms approximately 1 day sooner, occasionally cause nausea and vomiting, and may not reduce hospitalizations. In these low-risk patients, use of neuraminidase inhibitors remains optional. However, in those at risk for complications, hospitalization, or death, the totality of evidence from observational and clinical trials continues to support routine early use of neuraminidase inhibitors (3).


Marek Smieja, MD, PhD
McMaster University
Hamilton, Ontario, Canada
Hernán MA, Lipsitch M.  Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clin Infect Dis. 2011;53:277-9. 21677258
PubMed
 
Hsu J, Santesso N, Mustafa R, et al.  Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156:512-24. 22371849
PubMed
 
Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America.  Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1003-32. 19281331
PubMed
 

Figures

Tables

References

Hernán MA, Lipsitch M.  Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clin Infect Dis. 2011;53:277-9. 21677258
PubMed
 
Hsu J, Santesso N, Mustafa R, et al.  Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156:512-24. 22371849
PubMed
 
Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America.  Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1003-32. 19281331
PubMed
 

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