Nguyen-Van-Tam, Jonathan S.

Nicholson, K.G.

Openshaw, Peter J.M.

Repository@Nottingham

Letter of reply to Lancet 14-4111 1  2 Sir 3  4 Del Mar et al. assert that their recent Cochrane review was based on full clinical study 5 reports of all manufacturer-sponsored randomized trials. In fact, only a subset (46 of the 107 6 Clinical Study Reports obtained) were formally analysed.1 The study undertaken by Muthuri 7 et al. was indeed funded by Roche, but its design, conduct, interpretation and manuscript 8 preparation were conducted independently of the funder.2 Exhaustive attempts were made 9 to obtain datasets suitable for analysis from around the world. Compared with the 80 10 datasets received, relatively few (n=15) were not shared due to review board or 11 governmental restrictions (n=3) or inability to meet project timelines (n=12).2  None of the 12 contributors of data declared industry funding for the acquisition or assembly of their dataset.  13  14 We do not dismiss the findings in the Cochrane review. Indeed, the finding that there was no 15 signal suggesting that neuraminidase inhibitors (NIs) reduced serious complications1 is not 16 unexpected given that the clinical trials reviewed were conducted in community settings, 17 were based on mostly healthy patients suffering from mild influenza-like illness, and were not 18 designed or powered to assess impact on severe illness. Indeed, their assessment of 19 effectiveness of oseltamivir against hospital admission was based on 4 394 adults and 1 359 20 children; pneumonia – 4 452 subjects; and serious complications – 3 675.  Mortality, a 21 hallmark of pandemics and seasonal outbreaks, could not be assessed due to the absence 22 of deaths in the oseltamivir trials. The same limitations apply to the pooled analysis of 3 564 23 subjects in 10 RCTs of oseltamivir treatment by Kaiser et al,3 which unlike the Cochrane 24 review, showed that treatment was associated with reductions in influenza-related lower 25 respiratory complications and hospitalisation from any cause.   26  27 In contrast, the observational data assembled and analysed by Muthuri et al. used individual 28 participant data (an approach not pursued in the Cochrane review) and focused on patients 29 hospitalised with severe pandemic influenza A/H1N1 2009 infection (86% laboratory 30 confirmed).2 Many patients had risk-factors for severe illness; the dataset was extremely 31 large (n=29 234), and compared with no treatment, NI treatment was associated with a 32 reduction in mortality risk. 33  34 While we agree with Del Mar et al that randomised trials are less prone to error from bias 35 than observational studies,4 we do not accept that meta-analysis of existing RCTs, 36 conducted in community patients with “relatively benign influenza”,1 and which suffer 37 “problems in the design of many of the studies that were included”,1 can resolve pressing 38 questions about the role of NIs in the treatment or prevention of life-threatening influenza.  39  40 Thus, we reassert that the findings of the Cochrane Collaboration1 do not conflict with those 41 of the recent large observational study by Muthuri et al;2 rather, both studies reveal 42 beneficial effects of NIs in completely different scenarios (settings, severity, comorbidity and 43 background immunity). 44  45 Public outcry would indeed be justified if pandemic planners relied only on the available 46 RCTs when making decisions about how to prevent and treat severe influenza. 47  48  49 Jonathan S. Nguyen-Van-Tam 50 Peter J.M. Openshaw 51 Karl G. Nicholson 52  53 Conflicts of interest: unchanged since original Commentary was written 54  55 References 56  57  58 1. Jefferson T, Jones M, Doshi P, Del Mar C, Hama R, Thompson MJ, et al. Neuraminidase 59 inhibitors for preventing and treating influenza in healthy adults and children. 60 Cochrane Database Syst Rev 2014;4:CD008965. 61 2. Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TSA, Al Mamun A, et 62 al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted 63 to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual 64 participant data. The Lancet Respiratory Medicine 2014;2:395-404. 65 3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment 66 on influenza-related lower respiratory tract complications and hospitalizations. Arch 67 Intern Med 2003;163:1667-72. 68 4. Chalmers I. The development of fair tests of treatments. Lancet 2014;383:1713-14. 69 

Neuraminidase inhibitors for influenza complications: authors' reply

https://nottingham-repository.worktribe.com/738622/1/Letter of reply to Del Mar Lancet 14-4111_Final.pdf

Neuraminidase inhibitors for influenza complications: authors' reply

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