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

Stella G. Muthuri Sudhir Venkatesan Puja R. Myles Jo Leonardi-Bee Tarig S. A. Al Khuwaitir Adbullah Al Mamun Ashish P. Anovadiya Eduardo Azziz-Baumgartner Clarisa Báez Matteo Bassetti Bojana Beovic Barbara Bertisch Isabelle Bonmarin 1 Robert Booy Victor H. Borja-Aburto Heinz Burgmann Bin Cao 2 Jordi Carratala Justin T. Denholm Samuel R. Dominguez Pericles A. D. Duarte Gal Dubnov-Raz Marcela Echavarria Sergio Fanella Zhancheng Gao 3 Patrick Gérardin 4, 5, 6, 7 Maddalena Giannella Sophie Gubbels Jethro Herberg Anjarath L. H. Iglesias Peter H. Hoger Xiaoyun Hu Quazi T. Islam Mirela F. Jiménez Amr Kandeel Gerben Keijzers Hossein Khalili Marian Knight 8 Koichiro Kudo Gabriela Kusznierz Ilija Kuzman Arthur M. C. Kwan Idriss L. Amine Eduard Langenegger Kamran B. Lankarani Yee-Sin Leo Rita Linko Pei Liu Faris Madanat Elga Mayo-Montero Allison Mcgeer Ziad Memish Gokhan Metan Auksė Mickiene Dragan Mikić Kristin G. I. Mohn Ahmadreza Moradi Pagbajabyn Nymadawa Maria E. Oliva Mehpare Ozkan Dhruv Parekh Mical Paul Fernando P. Polack Barbara A. Rath Alejandro H. Rodríguez Elena B. Sarrouf Anna C. Seale Bunyamin Sertogullarindan Marilda M. Siqueira Joanna Skręt-Magierło Frank Stephan Ewa Talarek Julian W. Tang Kelvin K. W. To Antoni Torres Selda H. Törün Dat Tran Timothy M. Uyeki Annelies Van Zwol Wendy Vaudry Tjasa Vidmar Renata T. C. Yokota Paul Zarogoulidis Jonathan S. Nguyen-Van-Tam
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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Stella G. Muthuri, Sudhir Venkatesan, Puja R. Myles, Jo Leonardi-Bee, Tarig S. A. Al Khuwaitir, et al.. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: an individual participant data meta-analysis. Lancet Respiratory medicine, Elsevier, 2014, 2 (5), pp.395-404. 〈10.1016/S2213-2600(14)70041-4〉. 〈hal-01274568〉

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