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Meta-Analysis
. 2014 May;2(5):395-404.
doi: 10.1016/S2213-2600(14)70041-4. Epub 2014 Mar 19.

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

Stella G Muthuri  1 , Sudhir Venkatesan  1 , Puja R Myles  1 , Jo Leonardi-Bee  1 , Tarig S A Al Khuwaitir  2 , Adbullah Al Mamun  3 , Ashish P Anovadiya  4 , Eduardo Azziz-Baumgartner  5 , Clarisa Báez  6 , Matteo Bassetti  7 , Bojana Beovic  8 , Barbara Bertisch  9 , Isabelle Bonmarin  10 , Robert Booy  11 , Victor H Borja-Aburto  12 , Heinz Burgmann  13 , Bin Cao  14 , Jordi Carratala  15 , Justin T Denholm  16 , Samuel R Dominguez  17 , Pericles A D Duarte  18 , Gal Dubnov-Raz  19 , Marcela Echavarria  20 , Sergio Fanella  21 , Zhancheng Gao  22 , Patrick Gérardin  23 , Maddalena Giannella  24 , Sophie Gubbels  25 , Jethro Herberg  26 , Anjarath L Higuera Iglesias  27 , Peter H Hoger  28 , Xiaoyun Hu  29 , Quazi T Islam  30 , Mirela F Jiménez  31 , Amr Kandeel  32 , Gerben Keijzers  33 , Hossein Khalili  34 , Marian Knight  35 , Koichiro Kudo  36 , Gabriela Kusznierz  37 , Ilija Kuzman  38 , Arthur M C Kwan  39 , Idriss Lahlou Amine  40 , Eduard Langenegger  41 , Kamran B Lankarani  42 , Yee-Sin Leo  43 , Rita Linko  44 , Pei Liu  45 , Faris Madanat  46 , Elga Mayo-Montero  47 , Allison McGeer  48 , Ziad Memish  49 , Gokhan Metan  50 , Auksė Mickiene  51 , Dragan Mikić  52 , Kristin G I Mohn  53 , Ahmadreza Moradi  54 , Pagbajabyn Nymadawa  55 , Maria E Oliva  56 , Mehpare Ozkan  57 , Dhruv Parekh  58 , Mical Paul  59 , Fernando P Polack  60 , Barbara A Rath  61 , Alejandro H Rodríguez  62 , Elena B Sarrouf  63 , Anna C Seale  64 , Bunyamin Sertogullarindan  65 , Marilda M Siqueira  66 , Joanna Skręt-Magierło  67 , Frank Stephan  68 , Ewa Talarek  69 , Julian W Tang  70 , Kelvin K W To  71 , Antoni Torres  72 , Selda H Törün  73 , Dat Tran  74 , Timothy M Uyeki  75 , Annelies Van Zwol  76 , Wendy Vaudry  77 , Tjasa Vidmar  78 , Renata T C Yokota  79 , Paul Zarogoulidis  80 ; PRIDE Consortium Investigators; Jonathan S Nguyen-Van-Tam  81
Collaborators, Affiliations
Meta-Analysis

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

Stella G Muthuri et al. Lancet Respir Med. 2014 May.

Abstract

Background: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection.

Methods: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling.

Findings: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay).

Interpretation: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.

Funding: F Hoffmann-La Roche.

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Conflict of interest statement

Declaration of interests

Between October, 2007, and September, 2010, JSN-V-T did ad-hoc paid consultancy and lecturing for several influenza vaccine manufacturers (Sanofi Pasteur MSD, Sanofi Pasteur, GlaxoSmithKline, Baxter AG, Solvay, Novartis) and manufacturers of neuraminidase inhibitors (F Hoffmann-La Roche: oseltamivir [Tamiflu] and GlaxoSmithKline: zanamivir [Relenza]). He is a former employee of SmithKline Beecham (now part of GlaxoSmithKline), Roche Products (UK), and Sanofi Pasteur MSD, all before 2005. He has no outstanding interests related to shares, share options, or accrued pension rights in any of these companies. He is in receipt of current or recent research funding, related to influenza vaccination from GlaxoSmithKline and AstraZeneca and non-financial support (travel) from Baxter AG. His brother became an employee of GlaxoSmithKline in January, 2014. JL-B is Statistical Editor of the Cochrane Skin Group. PRM is the recipient of the unrestricted educational grant for research in the area of pandemic influenza from F Hoffman-La Roche, used to fund this work. She has also received travel grants from F Hoffman-La Roche and its subsidiaries to attend clinical seminars to present this work. RB has received financial support from CSL, Sanofi, GlaxoSmithKline, Novartis, Roche, and Wyeth to do research and present at scientific meetings. Any funding received is directed to an NCIRS research account at The Children’s Hospital at Westmead, NSW, Australia, and is not personally accepted by RB. All other named authors declare that they have no competing interests.

Figures

Figure 1:
Figure 1:. Study flow diagram
*47 overlapping data; one onset of illness before March 1, 2009 (Mexico); nine missing data for key variables.
Figure 2:
Figure 2:. Survival by time to treatment
HR=hazard ratio. NAI=neuraminidase inhibitor. *Cox regression shared frailty model (adjusted for treatment propensity and in hospital steroid or antibiotic use).
See this image and copyright information in PMC

Comment in

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