Date: December 16th, 2020
Reference: Butler et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. The Lancet 2020
Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the creator of the #FOAMed project called First10EM.com. He has a great new blog post about how we are failing to protect our healthcare workers during COVID-19.
Case: A 45-year-old female presents to her primary care clinician complaining of fever, sore throat and muscle aches. She did not get a flu shot this year. You diagnose her with an influenza-like illness (ILI). She wants to know if taking an anti-viral like oseltamivir (Tamiflu) will help?
Background: We covered oseltamivir six years ago in SGEM#98. This is still the longest Cochrane review (300+ pages) I have ever read (Jefferson et al 2014a). The overall bottom line was when balancing potential risks and potential benefits, the evidence does not support routine use of neuraminidase inhibitors like oseltamivir for the treatment or prevention of influenza in any individual.
There has been some controversy around oseltamivir. It was approved by licensing agencies and promoted by the WHO based on unpublished trials. None of those agencies had actually looked at the unpublished data. In fact, the primary authors of key oseltamivir trials had never been given access to the data – Roche just told them what the data supposedly said. Other papers were ghost-written (Cohen 2009). The BMJ was involved in a legal battle with Roche for half a decade trying to get access to that information. When they finally got their hands on the data, the conclusions of the reviews suddenly changed. After countries had spent billions stockpiling the drug, it turned out that oseltamivir had no effect on influenza complications, was not effective in prophylaxis, and had significantly more harms than originally reported (Jefferson 2014a; Jefferson 2014b). You can read more details about this controversy in the BMJ.
The oseltamivir issue is a great example of the problems with conflicts of interest (COI) in medical research. This is something I have spoken about often. It is not an ad hominem attack on any of the authors. Our current system of medical research involves industry funding. COIs are just another data point that needs to be considered. This is because the evidence shows COIs can introduce bias into RCTs, SRMA and Clinical Practice Guidelines. When I use the term bias I am referring to something that systematically moves us away from the “truth”.
There is specific evidence of bias in the oseltamivir literature. Dunn and colleagues looked at 37 assessments done in 26 systematic reviews and then compared their conclusions to the financial conflicts of interest of the authors. Among eight assessments where the authors had conflicts, seven (88%) had favourable conclusions about neuraminidase inhibitors. However, among the 29 assessments that were made by authors without conflicts, only five (17%) were positive (Dunn et al 2014).
The current best evidence shows that oseltamivir (Jefferson et al 2014a):
- Decreased time to first alleviation of symptoms by less than one day
- Does not statistically change hospital admission rate (1.7% vs 1.8%)
- Does increase nausea (NNH 28) and vomiting (NNH 22)
- Does increase neuropsychiatric events (NNH 94)
- Does increase headaches (NNH 32)
Clinical Question: Does oseltamivir improve time to recovery in patients presenting to their primary care clinician with an influenza-like illnesses?
Reference: Butler et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. The Lancet 2020.
- Population: Patients from 15 European countries over three influenza seasons who were one year of age and older and who presented to their primary care clinician with symptoms of influenza-like illness (ILI). ILI was defined as a “sudden onset of self-reported fever, with at least one respiratory symptom (cough, sore throat, or running or congested nose) and one systemic symptom (headache, muscle ache, sweats or chills, or tiredness), with symptom duration of 72 h or less during a seasonal influenza epidemic.”
- Exclusions: Chronic renal failure, substantial impaired immunity, patients in whom the treating clinician thought Tamiflu or admission to hospital was required, allergy, planned general anesthesia in the next two weeks, life expectancy less than six months, severe hepatic impairment, requirement for any live viral vaccine in the next seven days, and in some jurisdictions pregnant or lactating women.
- Intervention: Oseltamivir (Tamiflu)
- 75 mg by mouth twice daily for five days in adults and children more than 40 kg.
- For children (13 years or younger), oral suspension was given according to weight (children weighing 10–15 kg received 30 mg, >15–23 kg received 45 mg, >23–40 kg received 60 mg, and >40 kg received 75 mg).
- Comparison: Usual care
- Primary Outcome: Patient reported time to recovery based on daily symptom journals. Recovery was defined as having returned to usual daily activity and fever, headache, and muscle ache were rated as minor or no problem in key subgroups.
- Secondary Outcomes: Cost-effectiveness, hospital admissions, complications related to ILI, repeat attendance in general practice, time to alleviation of symptoms of ILI, incidence of new or worsening symptoms, time to initial reduction in severity of symptoms, use of additional symptomatic and prescribed medication, including antibiotic, transmission of infection within household, self-management of symptoms of ILI and adverse events/harms.
Authors’ Conclusions: “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.”
Quality Checklist for Randomized Clinical Trials:
- The study population included or focused on those in the emergency department. No
- The patients were adequately randomized. Yes
- The randomization process was concealed. Yes
- The patients were analyzed in the groups to which they were randomized. Yes
- The study patients were recruited consecutively (i.e. no selection bias). Unsure
- The patients in both groups were similar with respect to prognostic factors. Yes
- All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
- All groups were treated equally except for the intervention. Yes
- Follow-up was complete (i.e. at least 80% for both groups). Yes
- All patient-important outcomes were considered. No
- The treatment effect was large enough and precise enough to be clinically significant. No
Key Results: They enrolled 3,266 people from 15 European countries over three influenza seasons. Slightly more than half (52%) had a PCR-confirmed influenza infection.
- Primary Outcome: Time to recovery
- Mean benefit from oseltamivir was 1.02 days (95% [BCrI] 0.74 to 1.31)
- Some people may not have heard of the Bayesian Credible Interval (BCrI). It’s very much like the 95% confidence interval we talk about but reflects the fact that there is a big difference between Bayesian statistics and frequentist statistics. Bayesian statistics simply tell us that prior probability matters.
- Secondary Outcomes:
- No statistical differences identified in patient-reported repeat visits with health-care services, hospitalisations, x-ray confirmed pneumonia, or over-the-counter use of medication containing acetaminophen or ibuprofen
- More nausea or vomiting in the intervention group compared to usual group (21% vs. 16%)
1) Conflicts of Interest (COIs): Multiple authors reported COIs with Roche (make or oseltamivir). We already talked about this issue in the background material. We do not consider COI necessarily as a negative but rather a potential source of bias that needs to be considered when interpreting the literature. There is a good review on this issue of COI and reducing bias by Bradley et al in the JRSM 2020.
2) Blinding: The lack of blinding and the fact that the primary outcome is subjective are major limitations of this trial. With that combination, we expect significant bias. We expect that the patients given the fancy pill to think they are getting better (placebo effect), while the patient who were given nothing will have no impact or even feel worse.
In my mind, there is really no reason to design the trial this way. The authors say that they “deliberately chose to do an open-label trial in the context of everyday practice, because effect sizes identified by placebo-controlled, efficacy studies with tight inclusion criteria might not be reproduced in routine care. We also wished to estimate time to patient reported recovery from the addition of an antiviral agent to usual care rather than benefit from oseltamivir treatment compared with placebo.”
The logic here seems to be completely backwards. There is certainly a role for real world trials, because treatments often look worse in the real world, when medications are not always taken and patients are not so tightly selected. However, the existing evidence for oseltamivir is weak, so a trial designed to see a worse outcome in a real-world setting doesn’t make a lot of sense. More importantly, the desire to study oseltamivir combined with usual care has nothing to do with using a placebo or properly blinding a trial. There are many trials that compare usual care plus a treatment to usual care plus placebo. Deciding to make the trial unblinded simply introduces unnecessary bias.
Interestingly, they present data that strongly suggest the small effect they are seeing is entirely due to the placebo effect, although they fail to recognize it as such. Neuraminidase inhibitors work specifically on the enzyme neuraminidase, which is found on influenza A and B viruses. The enzyme is not found on other respiratory viruses, which is why we don’t use oseltamivir to treat other viral illness. However, these authors found that oseltamivir was equally effective whether or not the patient actually had the flu. The HR for patients with proven influenza was 1.27 as compared to an HR of 1.31 for patients with negative swabs. There may have been some false negative swabs in there, but this number demonstrates the placebo effect. There is no biological mechanism for oseltamivir to make patients without influenza better. They felt subjectively better because they were given a placebo, just like the patients who had influenza. This, to me, clearly demonstrates that the primary outcome was entirely placebo effect.
3) External Validity: This RCT was conducted in 15 European countries. There could be some differences between those countries and other countries in North America, Australia, Asia, Africa and Central and South America. With regards to Canada, last year the rate of influenza immunization was 42% for those 18 years of age and older and for those 12 years of age and older it was 34%. In this trial the vaccination rate was only 10%. Vaccination rates that are three to four times higher could decrease any potential efficacy of oseltamivir in our population.
4) Clinically Significant: They reported a potential benefit of one day that was statistically significant. This effect size is probably smaller and could even be zero given the unblinded nature of the RCT with self-reporting of a subjective outcome. We are very skeptical and do not have much confidence that there is any clinically significant benefit.
5) Harms: We cannot just consider the potential benefits but must also consider the potential harms. They did report an increased burden of nausea and vomiting in the oseltamivir group. This is consistent with the Cochrane 2014 SRMA. However, we could not find any evidence that they looked for any neuropsychiatric events. It is well recognized that harms/adverse events are systematically under-reported in studies and can lead to bias (Hodkinson et al BMJ 2013).
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We think the conclusions could have been more specific and less misleading. Perhaps something like, primary care patients with ILI who were treated in an unblinded trial with oseltamivir subjectively reported being better one day sooner compared to usual care alone. This came at a cost of an increase in nausea and vomiting.”
SGEM Bottom Line: We recommend getting a flu shot and not using oseltamivir.
Case Resolution: You provide her with some general advice about symptomatic treatment of an ILI. She is encouraged to stay home, wash her hands often and cover her mouth when she coughs. If her condition gets worse (ex: difficulty breathing, develops a rash, has a seizure) or is otherwise worried she can contact the office or consider going to the emergency department.
Clinical Application: We still do not have any high-quality evidence that supports the routine use of oseltamivir in the treatment of influenza or influenza-like illnesses.
What Do I Tell My Patient? Oseltamivir is unlikely to make you better quicker and can cause nausea, vomiting, and other side effects. I recommend against using it. Next year, think about getting the flu shot.
Keener Kontest: Last weeks’ winner was Dr. Richard Malthaner a thoracic surgeon from London, Ontario who was on SGEM#129 and SGEM#300. Thoracik knew abscess comes from the Latin abscessus which means to departure, withdrawal or congestion.
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- EM Literature of Note: Lies, Damned Lies, and Tamiflu (oseltamivir)
- Myths in EM: Still Prescribing Oseltamivir?