Journal ClubFLUshing Out the Evidence for Neuraminidase

Inhibitors in the Treatment of InFLUenza

Manish Khullar BSc.(Pharm)Sukhjinder Sidhu BSc.(Pharm)

Interior Health Pharmacy ResidentsInfectious Disease Rotation

May 1, 2014

2014

The Controversy

Influenza• Signs/symptoms– Fever– Sore throat– Rhinitis– Nonproductive cough– Myalgias– Malaise

• Complications – Secondary infections (bacterial pneumonia, otitis media)– Hospitalizations– Death

How does Oseltamivir Work?

Our PICODesign Meta-analysisPopulation Hospitalized patients with confirmed or suspected exposure

to influenza

Intervention Oseltamivir 75 mg PO bid x 5 daysComparator PlaceboOutcome Reducing mortality

Reducing morbidity (i.e. pneumonia)Reducing length of hospital stayMinimizing adverse events

Cochrane PICOD Meta-analysisP Hospitalized patients with confirmed or suspected exposure to

natural occurring influenza

I Oseltamivir- 20 RCTs

- 11 treatment (adults)- 4 treatment (children)- 5 prophylaxis

- F/U 6-42 days

Zanamivir- 26 RCTs

- 14 treatment (adults)- 2 treatment (children)- 10 prophylaxis

- F/U 5-35 daysC PlaceboO Many outcomes for prophylaxis, treatment, on-treatment and off-

treatment- Not mortality

Title

• Title does not state it’s a meta-analysis or systematic review

• Authors are Cochrane Collaboration Group – Can imply it’s at least a systematic review

Introduction

Rationale• Influenza antivirals are commonly used and stockpiled• Previous reviews have risk of reporting bias• On list of WHO essential drugsObjectives• potential benefits and harms of NIs for influenza in all

age groups… all clinical study reports of published and unpublished R, PC trials and regulatory comments

MethodsEligibility Criteria• Studies– NIs RCTs for prophylaxis, post-exposure prophylaxis

and treatment of influenza• Published and unpublished trials• Manufacturer-funded and non-manufacturer funded

clinical trials

– No specific length of follow-up considered– Exclusion criteria not identified

THOUGHTS?

Methods

Eligibility Criteria• Participants– Previously health children and adults– Exposed to naturally occurring influenza with or

without symptoms– Excluded people with illnesses with more

significant effects on the immune system (i.e. malignancy or HIV infection)

Methods

Information Sources• Electronic databases– CENTRAL, MEDLINE, MEDLINE (Ovid), EMBASE,

PubMed (NOT MEDLINE), DARE, NHSEED, HEED– January 2010 – July 2013

• Clinical study reports– Extensive searches conducted

• Regulatory information searches– Extensive searches conducted

MethodsSearch Strategy

Methods

Study Selection• 2 authors reviewed title & abstracts• 4 authors independently read all data– definitely include; definitely exclude; need more

information• 2 more authors reviewed for inclusion in Stage 1

MethodsStudy Selection• Stage 1 assessing the reliability and completeness

of trial data– authors discussed face-to-face each trial with comments

and other information from regulatory sources– decision to whether move trial to stage 2 via consensus

• Stage 2 satisfied following criteria:– completeness – CONSORT-specified methods &

specified results– internal consistency – external consistency

MethodsData Collection Process• Utilized a modified CONSORT statement-based

extraction template – 2 authors each searched oseltamivir and zanamivir trials– Disagreements were resolved amongst each other in

oseltamivir group and by a 3rd author in the zanamivir group

• For clinical study reports, complete list of trials were sent to manufacturers asking them to check accuracy and completeness of their list

Methods

Risk of Bias in Individual Studies• Used Cochrane “Risk of bias” tool• Review author judged risk of bias• Bias assessed at outcome and study level– Studies included had high risk of bias– Some outcomes from studies were poorly

documented/collected

Methods

Synthesis of Results• Chi2: test for heterogeneity • I2: level of statistical heterogeneity– Threshold for significance unknown

• Tau2: estimate of between-study variance• Combining data using random-effects

approachWHAT SHOULD THEIR THRESHOLD BE?

MethodsRisk of Bias Across Studies• Included unpublished trials

MethodsAdditional analyses• Subgroup analysis to investigate high estimates of

heterogeneity• Meta-regression to investigate pneumonia

heterogeneity • Sensitivity analysis– Fixed-effect method of Mantel and Haenszel to

supplement primary analyses using random-effects method

– Peto’s method used when sparse data and borderline sensitivity WHAT ANALYSES WOULD BE BENEFICIAL?

ResultsStudy Selection 208 studies identified

form various sources

123 studies excluded19 studies awaiting classification

66 studies for which clinical study reports requested

53 studies met eligibility5 trials excluded due to incompleteness2 trials excluded as didn’t fit inclusion criteria 46 trials included

- 20 oseltamivir- 26 zanamivir

ResultsRisk of Bias within Studies• Presented selection, attrition, reporting,

performance and detection bias– To address issue of reporting bias, they ignored

published trial reports if clinical study reports and regulatory information were available

– Random sequence generation missing in many trials– Blinding may have been affected in many trials– Placebos may have contained active substances

Results

• No analysis conducted on mortality outcome– Discussed deaths in the oseltamivir and zanamivir

arms, but no statistical analyses completed

THOUGHTS?

Time to First Alleviation of Symptoms in Adult Treatment (ITT Population)

Oseltamivir vs. Placebo

Clinically significant reduction?When to use random vs. fixed effects?

Time to First Alleviation of Symptoms in Adult Treatment (ITT Population)

Oseltamivir vs. Placebo

Complication: PneumoniaOseltamivir vs. Placebo

Complication: PneumoniaOseltamivir vs. Placebo

NNT = 100

Nausea in Adult Treatment (On-Treatment)Oseltamivir vs. Placebo

Nausea in Adult Treatment (On-Treatment)Oseltamivir vs. Placebo

NNH = 28

Vomiting in Adult Treatment (On-Treatment)Oseltamivir vs. Placebo

Vomiting in Adult Treatment (On-Treatment)Oseltamivir vs. Placebo

NNH = 22

Results

Risk of Bias Across Studies• No funnel plot or Egger’s test done to rule out

publication bias – Made every effort to minimize publication bias by

including non-published trials• No discussion on bias across studies, only bias

within studies

SHOULD WE BE WORRIED ABOUT PUBLICATION BIAS?

ResultsAdditional Analysis• Subgroup analysis– Time to first alleviation of symptoms in adults by

infection status– Pneumonia (diagnosis vs. non-diagnosis)

Discussion

Summary of Evidence• NIs have small, non-specific effects on reducing

time to alleviation of influenza-like illness symptoms in adults

• Treatment trials… do not settle the question of whether complications of influenza, such as pneumonia are reduced

• Use of oseltamivir increases the risk of adverse events such as nausea, vomiting…

Discussion

Conclusions• … appears to be no evidence for patients,

clinicians or policy-makers to use these drugs (NIs) to prevent serious outcomes

• Implications for future research– More effective preventative measures– Early identification of complications

Limitations• Did not formally assess mortality outcome• Effect of complications was based on unclear and

potentially unreliable definitions• Included many trials with high risk of bias– Affects validity of the results

• Authors do not summarize results in the context of observational study results that are driving standard of care in influenza treatment

• A generalized conclusion is made without taking severity of illness into account

Our Conclusions

• Population studied was broad– Not generalizable to specific groups– Doesn’t address the question of whether to give

NIs in high risk patients• More reviews needed to draw definite

conclusions about mortality and reductions in complications

• More reviews needed in severe influenza (i.e. critical care patients)

Your Conclusions?

IDSA Cochrane