Abstract
BackgroundThe value of neuraminidase inhibitors (NAIs) in reducing severe clinical outcomes from influenza is debated. A clinical trial to generate better evidence is desirable. However, it is unknown whether UK clinicians would support a placebo-controlled trial. A survey was conducted to determine the attitude of clinicians towards a clinical trial and their current practice in managing adults admitted to hospital with suspected influenza.MethodsSenior clinicians (n = 50) across the UK actively involved in the care of patients hospitalised with severe respiratory infections and/or respiratory infection research were invited to participate in an on-line survey. Participants were asked their opinion on the evidence for benefit of NAIs in influenza, their current practice in relation to: a) testing for influenza; b) treating empirically with NAIs; and c) when influenza infection is virolologically confirmed, prescribing NAIs.ResultsThirty-five (70%) of 50 clinicians completed the survey. Respondents were drawn mainly from infectious diseases, intensive care and respiratory medicine. Only 11 (31%) of 35 respondents agreed that NAIs are effective at reducing influenza mortality; 14 (40%) disagreed, 10 (28.6%) neither agreed nor disagreed. When managing adults admitted to non-ICU wards with a respiratory infection during an influenza season, 15 (51.7%) clinicians indicated they would usually perform a test for influenza in greater than 60% of patients but only 9 (31%) would treat empirically with NAIs in greater than 60% of patients. Few clinicians would either test or empirically treat patients presenting with other (non-respiratory infection related) diagnoses. If influenza infection is confirmed, 17 (64.5%) clinicians would prescribe NAIs in greater than 80% of patients with a respiratory infection treated on non-ICU wards Thirty-one (89%) clinicians agreed that a placebo-controlled clinical trial should be conducted and 29 (85%) would participate in such a trial.ConclusionsThere is strong support from UK clinicians for a placebo-controlled trial of NAI treatment in adults hospitalised with suspected influenza. Current variation in medical opinion and clinical practice demonstrates collective equipoise, supporting ethical justification for a trial. Low use of NAIs in the UK suggests randomisation of treatment would not substantially divert patients towards placebo.
Highlights
The value of neuraminidase inhibitors (NAIs) in reducing severe clinical outcomes from influenza is debated
Based on evidence generated from randomised controlled trials (RCTs) and subsequent meta-analyses, there is general consensus that NAI treatment in uncomplicated seasonal influenza is associated with a reduction in symptom duration of influenza illness by several hours. [6, 7] interpretation of the mechanism of this effect differs; the Cochrane group suggested that oseltamivir had no specific antiviral effect, while the Roche-funded review group found that benefit with oseltamivir was limited to the intention-to-treat-infected group suggesting a specific effect on the influenza virus. [6, 7]
No relevant placebo-controlled RCTs are available to directly inform the debate, instead, the strongest evidence is derived from large observational cohorts, dominated by studies of the use of NAIs for the treatment of pandemic influenza A(H1N1)pdm09. [6,7,8] An individual participant data (IPD) meta-analysis of data from 78 different observational studies, which included > 29,000 patients, found that the odds of death for adults treated with NAIs within 48 h of symptoms onset, compared to untreated adults was 0.50
Summary
The value of neuraminidase inhibitors (NAIs) in reducing severe clinical outcomes from influenza is debated. Based on evidence generated from randomised controlled trials (RCTs) and subsequent meta-analyses, there is general consensus that NAI treatment in uncomplicated seasonal influenza is associated with a reduction in symptom duration of influenza illness by several hours. No relevant placebo-controlled RCTs are available to directly inform the debate, instead, the strongest evidence is derived from large observational cohorts, dominated by studies of the use of NAIs for the treatment of pandemic influenza A(H1N1)pdm. [6,7,8] An individual participant data (IPD) meta-analysis of data from 78 different observational studies, which included > 29,000 patients, found that the odds of death for adults treated with NAIs within 48 h of symptoms onset, compared to untreated adults was 0.50 (95% CI 0.37–0.67). In reviewing the evidence for NAI use in influenza, an independent steering group of the Academy of Medical Sciences, supported by the Wellcome Trust, acknowledged that observational studies are generally at higher risk of bias than RCTs, that did not necessarily invalidate the evidence generated by such studies. [10] The report supports the use of NAIs for the treatment of patients hospitalised with influenza, whilst at the same time recognising that the strength of evidence surrounding the effectiveness of NAIs in reducing influenza mortality is sub-optimal and recommending that, in order to improve the evidence base, a RCT investigating the effectiveness of NAI treatment in reducing influenza mortality should be a research priority
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