Abstract
BackgroundObservational studies claimed reducing effects of neuraminidase inhibitors (NI) on hospital mortality in patients with H1N1 influenza A. It has been criticized that such findings are prone to common and serious survival biases.MethodsWith observational data from the FLU-CIN study group, multi-state and dynamic prediction models have been used to avoid such biases. The data included 1391 patients with confirmed pandemic influenza A/H1N1 infection collected during 2009-2010 in the UK. Due to their close relationship, the main outcome measures were hospital death and length of hospital stay.FindingsThere is no direct effect of NI on the hospital death rate; the hazard ratio (HR) of NI was 1.03 (95%-CI: 0.64–1.66). The discharge rate is increased for NI patients (HR = 1.89 (95%-CI: 1.65–2.16)) indicating that NI-treated patients stay shorter in hospital than NI-untreated patients, on average 3.10 days (95%-CI: 2.07–4.14). We also showed that the initiation timing of NI treatment (≤ 2 days versus > 2 days after onset) made no difference on the effects on the hospital death and discharge hazards. The hazard ratios remain stable after adjusting for potential confounders measured at admission (such as comorbidities and influenza-related clinical symptoms).ConclusionsThe potential beneficial effect of NI on hospitalized patients in the UK is rather a reduction of the length of hospital stay than a reduction of the mortality rate. There seems to be no confounding by indication and no differences if NI is given early or late. Different effects could be present in other populations (such as non-hospitalized individuals) or countries. Careful interpretation of the effect on length of hospital stay is needed due to potentially different discharge policies of NI-treated and NI-untreated patients.
Highlights
In recent years, the influenza drug Oseltamivir, which is a neuraminidase inhibitor (NI) and marketed under the trade name Tamiflu, attracted considerable attention, after it was stockpiled extensively by multiple governments to prepare for upcoming pandemics
The corresponding unadjusted hazard ratios (NI-treated vs. neuraminidase inhibitors (NI)-untreated) are HR = 1.03 (95%-CI: 0.64– 1.66) for hospital death and HR = 1.89 (95%-CI: 1.65–2.16) for hospital discharge. This means that the daily risk to die in hospital is similar for NI-treated and NI-untreated patients (HR = 1.03)
There is an effect on the hospital discharge hazard (HR(discharge) = 1.89) indicating that NI-treated patients stay shorter in hospital than NI-untreated patients
Summary
The influenza drug Oseltamivir, which is a neuraminidase inhibitor (NI) and marketed under the trade name Tamiflu, attracted considerable attention, after it was stockpiled extensively by multiple governments to prepare for upcoming pandemics. Using randomised controlled trials (RCTs), two large meta-analyses from members of the Cochrane collaboration found that the drug had very limited clinical effects on complications and viral transmission [2] and reduced the duration of symptoms by only about half a day [3]. It has been argued that such RCTs usually include only patients without a real clinical need [5] and they were not designed or powered to give results regarding serious complications, hospitalization and mortality [6]. Observational studies claimed reducing effects of neuraminidase inhibitors (NI) on hospital mortality in patients with H1N1 influenza A. It has been criticized that such findings are prone to common and serious survival biases
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