Manish Khullar BSc.(Pharm) Sukhjinder Sidhu BSc.(Pharm) Interior Health Pharmacy Residents

1. Journal ClubFLUshing Out the Evidence for Neuraminidase Inhibitors in the Treatment of InFLUenza Manish KhullarBSc.(Pharm) Sukhjinder Sidhu BSc.(Pharm) Interior Health Pharmacy Residents Infectious Disease Rotation May 1, 2014

2. 2014

3. The Controversy

4. Influenza • Signs/symptoms • Fever • Sore throat • Rhinitis • Nonproductive cough • Myalgias • Malaise • Complications • Secondary infections (bacterial pneumonia, otitis media) • Hospitalizations • Death

5. How does Oseltamivir Work?

6. Our PICO

7. Cochrane PICO

8. 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

9. Introduction Rationale • Influenza antivirals are commonly used and stockpiled • Previous reviews have risk of reporting bias • On list of WHO essential drugs Objectives • potential benefits and harms of NIs for influenza in all age groups… all clinical study reports of published and unpublished R, PC trials and regulatory comments

10. Methods Eligibility Criteria • Studies • NIs RCTs for prophylaxis, post-exposure prophylaxis and treatment of influenza • Published and unpublished trials • Manufacturer-funded and non-manufacturer funded clinical trials • No specific length of follow-up considered • Exclusion criteria not identified •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?

11. 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)

12. 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

13. Methods Search Strategy

14. 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

15. Methods Study 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

16. Methods Data Collection Process • Utilized a modified CONSORT statement-based extraction template • 2 authors each searched oseltamivir and zanamivirtrials • 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

17. 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

18. 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 approach • WHAT SHOULD THEIR THRESHOLD BE?

19. Methods Risk of Bias Across Studies • Included unpublished trials

20. Methods Additional 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?

21. Results Study Selection 208 studies identified form various sources 123 studies excluded 19 studies awaiting classification 66 studies for which clinical study reports requested 5 trials excluded due to incompleteness 2 trials excluded as didn’t fit inclusion criteria 53 studies met eligibility • 46 trials included • 20 oseltamivir • 26 zanamivir

22. Results Risk 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

23. Results • No analysis conducted on mortality outcome • Discussed deaths in the oseltamivir and zanamivir arms, but no statistical analyses completed • THOUGHTS?

24. Time to First Alleviation of Symptoms in Adult Treatment (ITT Population)Oseltamivir vs. Placebo

25. Time to First Alleviation of Symptoms in Adult Treatment (ITT Population)Oseltamivir vs. Placebo • Clinically significant reduction? • When to use random vs. fixed effects?

26. Complication: PneumoniaOseltamivir vs. Placebo

27. Complication: PneumoniaOseltamivir vs. Placebo NNT = 100

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

29. Nausea in Adult Treatment (On-Treatment)Oseltamivir vs. Placebo NNH = 28

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

31. Vomiting in Adult Treatment (On-Treatment)Oseltamivir vs. Placebo NNH = 22

32. 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?

33. Results Additional Analysis • Subgroup analysis • Time to first alleviation of symptoms in adults by infection status • Pneumonia (diagnosis vs. non-diagnosis)

34. 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…

35. 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

36. 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

37. 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)

38. Your Conclusions? Cochrane IDSA