Butler CC, van der Velden AW, Bongard E, et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. Lancet. 2020 Jan 4;395(10217):42-52. doi: 10.1016/S0140-6736(19)32982-4. Epub 2019 Dec 12. (Original study)

BACKGROUND: 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.

METHODS: 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.

FINDINGS: 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.

INTERPRETATION: 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.

FUNDING: European Commission's Seventh Framework Programme.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
Emergency Medicine 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Pediatrics (General) 6 / 7
Pediatric Emergency Medicine 6 / 7
Infectious Disease 5 / 7
Comments from MORE raters

Emergency Medicine rater

This large pragmatic trial found that patients who received oseltamivir self-reported being recovered 1 day sooner than those who did not. This is modestly more than the 16.8 hours difference that a Cochrane review found in their 2014 meta-analysis. While this trial enrolled a broader range of patients than the studies included in the Cochrane review, the increased effect size could easily be explained by the lack of any attempt at blinding. This is especially important since the outcome was by unblinded patient report and was subjective (return to usual activity with fever, headache, and muscle aches rated as "minor"). Importantly, there were no differences in most important secondary outcomes such as hospitalization or pneumonia. Duration of illness benefits appeared to be more marked for the comorbid elderly, at higher risk with longer duration of illness. Unfortunately, the lack of blinding results is a missed opportunity to add significant clarity to this contentious issue.

Emergency Medicine rater

Reaffirms previous research showing 1-day improvement with antivirals in flu.

General Internal Medicine-Primary Care(US) rater

Older persons and those with comorbidities and higher severity of influenza illness benefit the most. In my practice, however, even healthy individuals with mild-to-moderate symptoms usually want to take the antiviral medication to get better even a day quicker.

General Internal Medicine-Primary Care(US) rater

It is important for clinicians to know that the absolute benefits (in time to full recovery) are greater in older adults, especially if symptoms are severe and comorbidities are present. Also, the benefits in this group are substantial even if treatment is started 48-72 hours after illness begins.

Infectious Disease rater

There has been some debate about the usefulness of treating influenza. This study should help encourage primary care providers to prescribe antivirals, especially since it helps to define who might benefit most in what seems to becoming a heavy flu season.

Pediatric Emergency Medicine rater

Antiviral agents, particularly oseltamivir, are frequently prescribed to alleviate the symptoms and reduce the course of influenza. This study provides evidence that the average benefit for many patients is modest, and it reduces the duration of illness for only one day. This information should be considered when prescribing these agents.
Comments from EvidenceAlerts subscribers

Dr. Weijen Chang (3/1/2020 12:19 PM)

Agree with Dr Plaza!

Dr. Joachim Lelievre (2/3/2020 3:10 AM)

Does Oseltamivir prevent influenza mortality or severe morbidity (acute respiratory complication...)?
Without those kind of outcomes, I think it's difficult to pronounce anything about the efficacy of such a drug.

Dr. Martín Plaza (12/21/2019 8:24 AM)

Another attempt from the pharmaceutical industry to increase the prescription of oseltamivir, despite using an open-label methodology. They try to make it look as though oseltamivir is actually good. The reasons for an open-label study are unconvincing. There is a proven placebo effect (https://dx.doi.org/10.1370%2Fafm.1250), so a placebo-controlled trial is a must. The relative risk for vomiting and nausea is 1.30 (95% CI 1.12-1.52) for the group with oseltamivir (not presented in the results, I had to do the maths), which means that vomiting and nausea increase by 30% using oseltamivir and the number needed to harm is 20 (95% CI 13-46). Shared decision-making is probably the best choice here but if someone asks my opinion, I wouldn´t take the pill, neither would my three-year-old daughter.