Paper: Butler CC 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. PMID: 31839279
Clinical Question: Does adding antiviral treatment to usual primary care for patients with influenza-like illness reduce the time to recovery?
What They Did:
- Open-label, pragmatic, adaptive, randomized controlled trial
- 15 European countries during three seasonal influenza seasons
- Patients presenting with influenza like illness to primary care randomized to:
- Oseltamivir 75mg PO BID x5d + usual care
- For children <13 years oseltamivir given in oral suspension according to weight:
- 10 – 15kg: 30mg
- >15 -23kg: 45mg
- >23 – 40kg: 60mg
- >40kg: 75mg
- Usual care alone
- For children <13 years oseltamivir given in oral suspension according to weight:
- Trial designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity
- Patients stratified by:
- Age: <12, 12 – <65, and ≥65 years
- Overall severity of influenza-like illness: mild, moderate, or severe)
- Relevant comorbidity: yes or no for heart disease, diabetes, chronic respiratory condition, hepatic, hematological, neurological or neurodevelopmental condition, stroke or TIA, or overnight hospital stay in previous year
- Duration of symptoms since onset: ≤48hrs or >48 to 72hrs
- Oseltamivir 75mg PO BID x5d + usual care
Outcomes:
- Primary: Time to recovery as recorded on a daily journal
- Defined as return to usual activities, with fever, headache, and muscle aches minor or absent
- Secondary:
- Cost-effectiveness of adding antiviral treatment to usual primary care
- Incidence of hospital admissions
- Complications related to influenza-like illness
- Repeat attendance in general practice
- Time to alleviation of symptoms of influenza-like illness
- Incidence of new or worsening symptoms
- Time to initial reduction in severity of symptoms
- Use of additional symptomatic and prescribed medication
- Transmission of infection within household
Inclusion:
- Age ≥1 year
- Symptoms of influenza-like illness
- Defined as: sudden onset of self-reported fever, with at least:
- One respiratory symptom (cough, sore throat, or runny/congested nose)
- One systemic symptom (headache, muscle ache, swets/chils, or tiredness)
- With symptom duration of ≤72hrs during a seasonal influenza epidemic
- Defined as: sudden onset of self-reported fever, with at least:
Exclusion:
- Chronic renal failure
- Substantially impaired immunity (i.e. long-term oral steroids, chemotherapy, or immune disorder)
- Patients who should be prescribed immediate antiviral treatment or immediate hospitalization in the opinion of the responsible clinician
- Allergy to oseltamivir
- Scheduled for elective surgery or other procedures requiring general anesthesia during the subsequent 2 weeks
- Life expectancy estimate of <6 months
- Severe hepatic impairment
- Unable to be randomized within 72 hours after onset of symptoms
- Requirement for any live viral vaccine in the next 7 days
- Pregnant/lactating/breast feeding women
Results:
- 3266 participants recruited
- 3059 participants included for the primary outcome
- 1590 (52%) participants had confirmed influenza infection
- 2151 (66%) participants randomized within 48hrs of symptom onset
- Flu vaccination present in 10% of the population
- 96% of participants initiated oseltamivir treatment and 80% reported completing the full course
- Overall people returned to usual activities with mild residual symptoms minimally interfering after about 6.5 days.
- Overall time to recovery shorter with oseltamivir (Primary Outcome):
- 1.02 days (95% [BCrI] 0.74 to 1.31)
- HR 1.29; 95% Bayesian credible interval (BCrI) 0.74 to 1.31
- Estimated mean benefit from oseltamivir:
- Pts <12 years: 0.70 (95% [BCrI] 0.30 to 1.20)
- Pts ≥65 years: 3.20 (95% [BCrI] 1.00 to 5.50)
- Estimated mean benefit from oseltamivir in influenza vs non-influenza diagnosis was similar regardless of influenza status
- No differences identified in patient-reported repeat visits with health-care services, hospitalizations, or x-ray confirmed pneumonia
- Reports of new infections within the household:
- Oseltamivir + Usual Care: 39%
- Usual Care Alone: 45%
- Absolute Difference 6.0%; 95% CI 2.1 to 10.0
- Incidence of new or worsening nausea/vomiting:
- Oseltamivir + Usual Care: 21.0%
- Usual Care Alone: 16.0%
Strengths:
- Important to note that the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report
- Groups were very well balanced in terms of age, comorbidity, severity of influenza-like illness, and symptom duration
Limitations:
- This was an open-label study, with no placebo used and drugs not masked. This has huge implications in bias of a subjective outcome
- Non-consecutive recruitment. Only 5500 patients over 3 years of influenza. This creates a selection bias
- Standard care was not standardized. We don’t know anything about other medications used as far as how often, and what doses
- More antibiotics used in the usual care group
- Clinicians assessment of severity of influenza-like illness as mild, moderate, or severe was not well defined (i.e. subjective)
- ≈5500 patients were eligible, however 2235 were excluded with nearly half not willing or able to comply with the trial. We have no idea what happened to these patients
- Majority of patients were in the 12 to 65-year age group. Only 14% were < 12 years and 6% in the ≥ 65 years.
- Participants only recorded symptoms once a day, therefore smaller intervals of time (i.e. hours) may not have been detected
- The primary outcome is a subjective one (thresholds for returning to work may be different for different people)
- Only 10% of the participants were vaccinated for influenza. There could be a lesser effect seen in a population where vaccination is performed more regularly
Discussion:
- Overall, people returned to usual activities with mild residual symptoms after about 6.5 days. The addition of oseltamivir decreased this by about 1 day overall (which is consistent with previous evidence).
- Older, sicker, patients with comorbid conditions, or longer previous symptom duration could expect to return to usual activities with mild residual symptoms 2 to 3 days earlier with oseltamivir
- The biggest issue in this trial is non-blinding in a study with a self-reported, soft, subjective outcome. Everyone knew what they were taking.
- 10% of population got influenza vaccination. This is an extremely low rate. Looking at the CDC website (Link is HERE), in adults, 18 years of age and older, there was an overall ≈40% vaccination rate in the US (2010 – 2019). Although the flu vaccine is not perfect, it reduces flu illness, hospitalizations, and deaths. In a study with no objective benefits (i.e. hospitalization, pneumonia), it seems focusing on vaccination would be more beneficial than feeling better 1 or 2 days sooner.
- In this trial participants with confirmed influenza did not benefit more than those testing negative
- As the flu swab does not have 100% sensitivity, there may have been some false negatives in the non-confirmed influenza group
- Inconsistent swabbing techniques could have also affected this
- Effectiveness of oseltamivir in the influenza negative patients raises concerns about validity of the outcomes
- Interestingly in this study, oseltamivir started after 48 hours after symptom onset had a similar effect as the patients who started it <48 hours
Author Conclusion: “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.”
Clinical Take Home Point: This study should not change practice. In a non-blinded study with a subjective outcome, we would expect patients who are getting the “fancy pill” to feel better faster. Additionally…
- Oseltamivir works on neuraminidase. This enzyme is not found on other viruses, and there is no biological mechanism for it to have an effect in these patients
- Objective outcomes of hospitalization and x-ray confirmed pneumonia showed no benefit with oseltamivir
- There is an increase in nausea/vomiting in the patients taking oseltamivir
References:
- Butler CC 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. PMID: 31839279
For More Thoughts on This Topic Checkout:
- REBEL EM: The Tamiflu Debacle
- REBEL Review 80: Oseltamivir (Tamiflu) for Treatment of Influenza
- First10EM: Tamiflu Doesn’t Work
- The SGEM: SGEM #312 – Oseltamivir is Like Bad Medicine – For Influenza
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
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