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InfluenzaOver the last 5 years, the use of neuraminidase inhibitors for the treatment of influenza has skyrocketed. Emergency physicians have been pushed to prescribe these medications under the belief that they reduced symptoms, the risk of complications, hospitalizations, and transmission. However, the recommendation for the use of these drugs has never sat on firm evidence-based ground. So what did we know then, and what do we know now?

Background

A prior Cochrane review published in 2012 noted that much of the data was unavailable for them to review as it was not released by Roche pharmaceuticals [1]. The available data only supported a reduction in symptoms but marketing focused on reduction in complications and transmission. Many physicians have remained skeptical of the utility of these drugs. Why? Well, what we’ve always known is that the complete set of data and studies was never released.

What’s New?

Last week the BMJ published two systematic reviews on these drugs (via the Cochrane Acute Respiratory Infections Group) along with a number of editorials on the topic. With full access to the data, the blinders are off. We have a full picture of the data, and it doesn’t look good… at least not for oseltamivir (Tamiflu) and zanamivir (Relenza). Let’s take a look at each systematic review.

Article #1: Oseltamivir (Tamiflu)

Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2545. [2]

Design: Systematic review of RCTs on adults and children

Main outcome measure: Time to alleviation of symptoms, complications, hospital admissions and adverse events

Outcome measure
Finding
Alleviation of symptomsShortened by 16.8 hours with oseltamivir
Admission to hospitalNo difference
Reduction in confirmed pneumoniaNo difference
Other complicationsNo difference
Transmission in prophylaxis groupNo reduction
Side Effect
Results
NauseaIncreased (NNH 28)
VomitingIncreased (NNH 22)
Psychiatric eventsIncreased (NNH 94)
HeadacheIncreased (NNH 32)

* NNH = Number needed to harm  

Summary: Oseltamivir led to a minor decrease in time to symptom alleviation with no benefit for complications, hospitalization or transmission. Side effects were common.

Article #2: Zanamivir (Relenza)

Heneghan CJ, Onakpoya I, Thopson M, Spencer EA, Jones M, Jefferson T. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2547. [3]

Design: Systematic review of RCTs on adults and children

Main outcome measure: Time to alleviation of symptoms, complications, hospital admissions and adverse events 

Outcome Measure
Finding
Alleviation of symptomsShortened by 14.4 hours with zanamivir
Admission to hospitalNo data
Reduction in confirmed pneumoniaNo difference
Other complicationsNo difference
Prophylaxis1.98% reduction in symptomatic influenza (NNT 51)
 

Summary: Zanamivir led to a minor decrease in time to symptom alleviation with no benefit for complications or hospitalizations. There was a small decreased in transmission. Zanamivir was well tolerated without any major side effects seen in this data set.

Conclusions from these articles

Oseltamivir and zanamivir treatment showed modest decreases in time to symptom alleviation in comparison to placebo. However, there was no comparison made to standard supportive therapy for reduction of symptoms. A little acetaminophen or NSAID may be just as effective. Additionally, neither medication reduced the risk of complications or any other clinically important outcomes. Oseltamivir frequently led to side effects that may be worse than influenza itself. Lastly, prophylaxis was ineffective with oseltamivir and showed only modest benefits with zanamivir.

Editorial

In addition to the two Cochrane Acute Respiratory Infections Group publications, the BMJ published an accompanying editorial [4]. The authors discuss a number of issues but focus on the fact that despite this drug being approved for use for the last 15 years, we’ve never had access to the full data set. Roche pharmaceuticals left scores of data unpublished and, more insidiously, selectively published the studies that supported the use of the drug. The result is that billions have been spent on these drugs for treatment of influenza, prevention in close contacts of patients with influenza, and in creating stockpiles of medications in the event of an epidemic or pandemic. These issues have been picked up in the mainstream media (The Guardian editorial) as well.

We, as clinicians should demand more transparency. It would seem reasonable for regulatory organizations to require the disclosure of all data, not just published data, before approving a drug.

 

References 

  1. Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children (Review). Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub3.
  2. Heneghan CJ, Onakpoya I, Thopson M, Spencer EA, Jones M, Jefferson T. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2547.
  3. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2545
  4. Krumholz HM, Hines HH. Neuraminidase inhibitors for influenza: The whole truth and nothing but the truth. BMJ 2014; 348: g2548.

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Anand Swaminathan, MD MPH
Assistant Professor Emergency Medicine
Assistant Residency Director
Bellevue/NYU Emergency Department