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Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

Christopher C Butler, Alike W van der Velden, Emily Bongard, et al

Lancet Published: December 12, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)32982-4

Background 背景

Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.

欧洲初级医疗中很少针对流感样症状使用抗病毒药，多数原因在于认为治疗无效且尚未经过独立的临床试验确定从治疗中获益的人群。我们旨在确定针对流感样症状的患者，在常规初级医疗的基础上加用抗病毒药能否缩短所有患者及关键亚组患者病情康复的时间。

Methods 方法

We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.

我们进行了一项开放标签、实效性、适应性设计、随机对照临床试验，对于年龄在1岁以上就诊于初级医疗的流感样症状患者，在常规治疗的基础上加用奥司他韦。主要预后终点为病情康复的时间，定义为恢复日常活动且仅有轻度或无发热、头痛及肌肉疼痛。根据Bayes分段指数主要分析模型，试验设计及样本量足以评估奥司他韦对于总体样本及36个预先确定亚组（年龄，基础疾病，症状持续时间及症状严重程度）的疗效。试验在ISRCTN 注册，注册号ISRCTN 27908921。

Findings 结果

Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20–1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74–1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30–1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00–5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.

在2016年1月15日至2018年4月12日间的三个流感季中，我们在欧洲15个国家纳入了3266名患者，1629名分至常规治疗加用奥司他韦组，1637名分至常规治疗组，并分别在1533名 (94%) 和 1526名 (93%)患者评价主要预后终点。3059名患者中的1590名 (52%) 经PCR确诊为流感感染。奥司他韦组患者病情恢复时间较短 (风险比 1·29, 95% Bayesian 可信限 [BCrI] 1·20–1·39)，且在36个预先确定亚组中的30个也得到相同结果，风险比从 1·13 到 1·72。奥司他韦治疗获益绝对值为 1·02 天 (95% [BCrI] 0·74–1·31)，在各个预先确定的亚组获益为12岁以下、病情较轻、无基础疾病及发病时间较短的患者 0·70 (95% BCrI 0·30–1·20) 天，年龄65岁以上且病情较重、有基础疾病及发病时间较长的患者 3·20 (95% BCrI 1·00–5·50) 天。奥司他韦组呕吐或恶心的发生率较高。

Interpretation 结论

Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner.

对于初级医疗就诊的流感样症状患者，与常规治疗相比，加用奥司他韦治疗能够使病情恢复平均提早1天。病情较重且有基础疾病及发病时间较长的老年患者病情恢复提早2-3天。

Funding 资助

European Commission's Seventh Framework Programme.