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Date: December 13th, 2014

Guest Skeptic: Marcus Prescott is a nurse from Norway. He works at the Trondheim University Hospital. His college thesis was called “Barriers and Facilitators to the implementation of evidence based practice among RNs in specialist health care”. Marcus is also a proud member of the Norwegian Skeptics’ Society and runs their Skeptics in the Pub events.

Case: 25 year-old nurse with no significant past medical history presents to the emergency department with a 48 hour history of aching all over, fever and cough. He did not get a flu shot this year. You diagnose him with a flu like illness and provide him with advice on management and set expectations. However, before leaving the emergency department he wants to know if taking one of those flu drugs he sees on the television will help?

Background: Influenza is a seasonal phenomenon and we have covered the flu before on SGEM#20 Hit Me with Your Best Shot when we discussed mandatory immunization for healthcare workers.

Immunization has been on of the most significant advances in modern medicine. Some vaccines have been highly successful (Haemophilus Influenzae B, small pox, polio) while others have been not as successful (HIV).  Some vaccines work well but are their effectiveness decreases with time (whooping cough).

The flu vaccine is one that is not highly effective. There are a number of reasons it is not as effective. However, there was a Cochrane review showed that vaccinating healthcare workers, in addition to other preventative interventions, might protect the elderly in long-term care facilities.

IMG_0091The evidence contained in the Cochrane review was not great and had high risk of bias. Evidence based medicine has limitations and sometimes the BEST evidence is not great. Despite the limited data it is still recommended healthcare workers get a flu shot.

Get a flu shot I’m Bat Doc…

This podcast is going to focus on a treatment option after you have been diagnosed with the flu rather than preventing it in the first place. Neura-mini-dase inhibitors are influenza antiviral drugs often used to treat patients with the flu. Many governments stockpiled these drugs with the H5N1 scare in 2005 and increased their supplies after the 2009 H1N1 pandemic.

There were concerns these drugs were not as effective as promoted by their pharmaceutical companies. Much of this skepticism came from all the data not being available to analyze.

Clinical Question: Do neuraminidase inhibitors benefit patients’ with influenza?

Reference: Jefferson et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children (Review).  Cochrane Database Syst Rev. 2014 Apr

  • Population: This review included 20 Oseltamivir (Tamiflu) trials with 9,623 participants and 26 Zanamivir (Relenza) trials with 14,628 participants. The participants were healthy people of all ages. Previously healthy includes people with chronic illness (such as asthma, diabetes or hypertension), but excludes illnesses with more significant effects on the immunes system (such as malignancy or HIV)
  • Intervention: Neuraminidase inhibitors (Oseltamivir or Zanamivir) administered by any route
  • Comparison: Note that placebos might contain active substance
  • Outcomes:
    • Primary Outcomes:
      1. Treatment Studies (Symptom relief, pneumonia and hospitalization)
      2. Prophylaxis Studies (Influenza or ILI, household transmission and hospitalizations)
      3. Harms (Nausea, vomiting, cardiac and psychiatric)
    • Secondary Outcomes:
      1. Treatment studies (Symptom relapse after finishing treatment, Drug resistance, Viral excretion and Mortality)
      2. Prophylaxis studies (Drug resistance, Viral excretion and mortality)

Authors’ Conclusions: “Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.”

checklist-cartoonQuality Check List 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. No
  7. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results:

Time to first symptom alleviation: Less than one day

  • Oseltamivir:
    • In adults reduced by 16.8 hours, from 7 to 6.3 days (-16.8 hours, 95% CI -25.10 to -8.42)
    • In healthy children reduced by 29 hours, based on one trial (-29 hours, 95% CI -12 to -47)
    • No significant effect in asthmatic children (+5.2 hours, 95% CI -11.1 to +21.4)
  •  Zanamivir:
    • In adults reduced by 14.4 hours, from 6.6 to 6.0 days (-0.60 days, 95% CI -0.81 to -0.39)
    • No significant effect in children (-1.08 days, 95% CI -2.32 to + 0.15)
    • Use of relief medication in the placebo-group showed a non-significant 0.41 day decrease
    • No significant difference in the influenza-infected and the non-influenza-infected subgroups (P = 0.53)

Hospitalizations: No difference

  • Oseltamivir:
    • No significant effect in treatment of adults (RR 0.92, 95% CI 0.57 – 1.50) or children (RR 1.92, 95% CI 0.70 to 5.23)
    • No significant effect in prophylaxis (RR 1.114, 95% CI 0.66 to 1.94)
  •  Zanamivir:
    • Hospitalisations were not reported in the trials

Pneumonia: No real difference

  • Oseltamivir:
    • Significantly reduced self reported, investigator mediated, unverified pneumonia (RR 0.55, 95% CI 0.33-0.90, NNTB = 100)
    • Not significant in trials with detailed diagnostic criteria or radiological confirmation of pneumonia. (RR 0.69, 95% CI 0.33 – 1.44)
    • No significant effect in children (RR 1.06, 95% CI 0.62-1.83)
  •  Zanamivir:
    • Not significant in X-ray confirmed pneumonia (RR 1.02, 95% CI 0.35 – 3.02)
    • Not significant when including self reported, investigator-mediated, unverified outcome (RR 0.90, 95% CI 0.58-1.40)
  • In meta-regression of “pneumonia”, treatment effects were not statistically different by age (P = 0.22), drug (P = 0.89) or indication (P = 0.14), but by method of diagnosis (P = 0.025)

Bronchitis, sinusitis and otitis media: No difference

  • Oseltamivir:
    • No significant effect on bronchitis (RR 0.75, 95% CI 0.56 – 1.01), sinusitis (RR 1.03, 95% CI 0.76 – 1.40) or otitis media (RR 1.11, 95% CI 0.57 – 2.15) in adults
    • No significant effect on bronchitis (RR 0.65, 95% CI 0.27 – 1.55), sinusitis RR 1.00, 95% CI 0.58 – 1.72) or otitis media (RR 0.80, 95% CI 0.62 – 1.02) in children
  •  Zanamivir:
    • Significantly reduced risk of bronchitis in adults (RR 0.75, 95% CI 0.61 – 0.91, NNTB = 56).
    • No significant effect on sinusitis (RR 1.12, 95% CI 0.84 – 1.48) or otitis media (RR 0.81, 95% CI 0.54 – 1.20) in adults.
    • No significant effect on bronchitis (RR 0.86, 95% CI 0.26 – 2.80), sinusitis (RR 0.87, 95% CI 0.12 – 6.45) or otitis (RR 1.00, 95% CI 0.59 – 1.72) in children.

Serious complications and study withdrawals: No difference

  • Oseltamivir:
    • No significant effect in adults (RR 0.91, 95% CI 0.40 – 2.06)
    • Could not be assed in prophylaxis due to lack of events
    • Could not be assessed in children due to lack of events
  •  Zanamivir:
    • No significant effect in adults (RR 1.10, 95% CI 0.46 – 2.63)
    • No significant effect in prophylaxis (RR 1.09, 95% CI 0.36 – 3.26)
    • Could not be assessed in children due to lack of events

Prophylaxis:

  • Oseltamivir:
    • Significant effect on symptomatic influenza in individuals (RR 0.45, 95% CI 0.30 to 0.67, NNTB = 33).
    • No significant effect for all other influenza outcomes
    • Significant effect on symptomatic influenza in household (RR 0.20, 95% CI 0.09 to 0.44, NNTB = 7), but no significant effect on asymptomatic influenza (RR 1.14, 95% CI 0.39 to 3.33)
    • Post-exposure prophylaxis could not be assessed because of poor trial methodology
  •  Zanamivir:
    • Significant effect on symptomatic influenza for individuals (RR 0.39, 95% CI 0.22 to 0.70, NNTB = 51))
    • Significant effect on symptomatic influenza in households (RR 0.33, 95% CI0.18 to 0.58, NNTB = 7)
    • No significant effect on asymptomatic influenza (RR 0.97, 95% CI 0.76 to 1.24)
    • No significant effect on asymptomatic individuals in post-exposure prophylaxis of households (RR 0.88, 95% CI 0.65 to 1.20)

Harms of Treatment:

  • Zanamivir: No significant increase in adverse events were reported
  • Oseltamivir:
  • Nausea, Vomiting and Diarrhea: More
    • Significantly increased risk of nausea (RR 1.57, 95% CI 1.14 to 2.15, NNTH = 28) and vomiting (RR 2.43, 95% CI 1.75 to 3.38, NNTH = 22) in adults
    • Significantly decreased risk of diarrhea (RR 0.67, 95% CI 0.46 to 0.98, NNTB = 43) in adults (though placebos might contain active ingredient that induces diarrhea)
    • Significantly increased risk of vomiting in children (RR 1.70, 95% CI 1.23 to 2.35, NNTH = 19).
  • Cardiac Effects: Unsure
    • May reduce cardiac events (RR 0.49, 95% CI 0.25 to 0.97, NNTB = 148), but may increase QTc-prolongation (RD 4.0%, 95% CI 0,71 to 7.30, NNTH = 25)
  • Psychiatric Effects: Perhaps (dose related)
    • No significant effect in treatment trials, but there was a dose response effect in two “pivotal” treatment trials between daily dosage of 150mg and 300mg (P = 0.038)
    • Significant effect in prophylaxis trials (RR 1.80, CI 1.05 to 3.08, NNTH 94)
  • Renal Effects: Perhaps
    • No significant effect (RR 3.17, CI 0.96 to 10.49, NNTH 150). Sensitivity analysis with Peto´s method gives significant result (P = 0.02)

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Rather than reviewing only easily accessible and published data, the reviewers managed to get a hold of the full clinical study reports (CSRs) from regulators and industry. This allows for full statistical re-analysis and assessment of bias. In turn it gives a more complete and accurate picture of the evidence.

Marcus Prescott

Marcus Prescott

CSRs are the intermediate stage between the full raw data collected from a clinical trial and the summarised articles published in the journals. They contain all the information needed to conduct data analysis on data, review bias and make conclusions. These do not include confidential patient information, except in certain easily redacted appendices. Though they should be public property, they are often withheld.

Oseltamivir and Zanamivir were licensed for marketing by the FDA and EMA around the turn of the millennium. Though they at first did not sell well, the H5N1 avian influenza outbreaks quickly brought the drug to blockbuster levels. Since their licensing, the governments of the world have accumulated stockpiles for over 9 billion dollars.

The stockpiling was based on the earlier claims that NIs might reduce the time to alleviation of symptoms somewhat, and more importantly reduce the risk of complications such as pneumonia or death

The 2006 version of this review (Jefferson et al 2006) supported these claims, showing limited effects on time to first alleviation of symptoms and complications. The authors advised against use in regular seasonal influenza, but supported use in endemic or pandemic settings.

During the Influenza A H1N1 p2009 outbreak governments commissioned an updated review from the Cochrane Collaboration. While working on this a comment on the Cochrane-website Japanese paediatrician pointed out that the results were based on only one industry run meta-analysis of ten studies, of which only two were published. Further investigation into trial registries, ethical review boards and regulatory documents showed several missing trials, trial programmes and missing data.

Inquiries by the Cochrane team were made to access the missing data, but for several years both industry and the relevant regulators continued to withhold the data. When they finally relented the Cochrane team reviewed the 2.2 GBs of data and regulatory comments to arrive at the review published in April 2014.

As seen in the main results here presented, they differed significantly from what was seen in the published data.

The effects of neuraminidase inhibitors in the treatment or prevention of influenza is in part difficult to assess because of major possible sources of bias in the trials.

There was generally incomplete outcome data for symptoms, complications and safety data; and a high degree of selective reporting. Many studies lacked random sequence generation. Blinding of participants and personnel was inadequate in most trials. The reviewers also report a high risk of other bias. Only allocation concealment and blinding of outcome assessment can be considered generally adequate.

Other commentary about this Cochrane review:

Comment on Authors’ Conclusion Compared to SGEM Conclusion: These are reasonable conclusions giving all the difficulties, limitations and data provided.

SGEM Bottom Line:

In children and adults treated with the neuraminidase inhibitors oseltamivir or zanamivir there is a significant reduction of time to symptomatic improvement. This effect was not seen in asthmatic children. Though the effect is statistically significant, it may not be clinically significant. It is unclear whether this is superior to commonly used antipyretics.

The evidence does not support claims of reduction in risk for major or minor complications, hospitalisation or death in healthy individuals or in individuals with higher risk of complications (such as children with asthma or the elderly).

The prophylactic effect seems minimal.

Neuraminidase inhibiotors increases the risk of adverse events such as nausea, vomiting, and perhaps psychiatric effects.

When balancing possible risks and benefits, the evidence does not support routine use of neuraminidase inhibitors for the treatment or prevention of influenza in any individuals.

Case Resolution: The nurse was told to stay home from work, drink plenty of fluids, take over the counter medications for aches and pains as needed, wash their hands well, cover their mouth when they cough, consider getting a flu shot next year and don’t stand so close to me.

Clinically Application: The evidence does not support the routine use of neuraminidase inhibitors in the treatment of influenza. The benefit of prophylactic use is debateable when balanced against the risk of adverse events. Exceptions might exist in compassionate cases.

What Do I Tell My Patient? This drug might reduce the length of time you are sick with the flu by about one day, but it might also make those days worse with more nausea and vomiting.

Keener Kontest: Last weeks winner was Scott Kobner from New York School of Medicine. Scott knew the largest kidney stone every removed according to the Guinness Book of World records was 13cm. I am not optimistic tamsulosin would have helped in passing this stone.

Listen to the SGEM this week for the Keener/Gunner Question. If you know the answer than send me an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

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