The Case Against Tamiflu

If flu-like symptoms have you reaching reflexively for oseltamivir, consider three things: the cost, its very limited efficacy and the problem of creating resistant strains of flu. EPM published a version of this article a year ago, but with one new study surfacing, and the ubiquity of Tamiflu, it bears repeating.

If flu-like symptoms have you reaching reflexively for oseltamivir, consider three things: the cost, its very limited efficacy and the problem of creating resistant strains of flu. EPM published a version of this article a year ago, but with one new study surfacing, and the ubiquity of Tamiflu, it bears repeating.

Last year fellow EPM regular David Newman wrote a piece for the Huffington Post with the oh-so-subtle title: “The News About Tamiflu: It Doesn’t Work.” He referenced many studies, including one by a very smart friend, Mark Ebell. Mark founded a literature review service that focused on high-quality clinical studies called Essential Evidence Plus that was ultimately sold to Wiley.

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So, was Newman right? Does oseltamivir work? Given that many were suspicious whether oseltamivir really produced benefit for flu patients, there was a move to get Roche to release their unpublished studies and raw data on Tamiflu (why would there be unpublished studies if they all showed that oseltamivir worked? Selective publication?). Many organizations petitioned for the data for years, but, according to Newman, it was finally released to my friend, Mark Ebell.

Ebell and his colleagues e-published in Family Practice in September of 2012 an analysis of the eight unpublished trials and the three published ones. The in-print version came out in April of 2013. The major results of the analysis were:

There was a reduction of symptoms of about 24 hours in patients confirmed to have the flu. This being the case, a cost-benefit analysis needs to be done to determine if spending $120 of somebody’s money (patient or insurance company) to buy one less day of illness is worth it. And that assumes that the conclusion of the authors is correct. One study showed that symptom reduction was 29 hours when started within 24 hours of onset, but only 15 hours if started between 24-36 hours of onset.

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Oseltamivir did not decrease hospitalizations, but pneumonia may have been a tad less common with treatment. Regarding side effects, nausea and vomiting have been reported with oseltamivir.

Not noted by the Ebell review are neurologic and psychiatric effects noted primarily in Japanese children 16 years of age or younger such as delirium, hallucinations, confusion, abnormal behavior, convulsions and encephalitis. The Japanese protocol for the use of oseltamivir in children is similar to the U.S. protocol. Theories as to why these effects have been essentially limited to Japanese children have been set forward but have not been substantiated.

EFFECTIVENESS OF OSELTAMIVIR IN ADULTS: A META-ANALYSIS OF PUBLISHED AND UNPUBLISHED CLINICAL TRIALS
Ebell, M.H., et al, Fam Pract 30(2):125, April 2013
METHODS: The authors, from the University of Georgia, performed a systematic review of eleven RCTs (4,769 patients over age 12), including eight unpublished studies (largely industry sponsored), comparing oseltamivir and placebo in patients with confirmed or suspected influenza.
RESULTS: The mean reduction in the duration of symptoms with active treatment was 20.7 hours in an intention-to-treat (ITT) population with clinically suspected influenza and 25.4 hours in an ITT population with laboratory-confirmed influenza (ITTI). Symptom reduction was less profound in adults older than 65. In one relevant study, the mean reduction in symptom duration was 28.8 hours when oseltamivir was started within 24 hours of onset, but 14.8 hours when started at 24-36 hours. Overall rates of hospital admission (reported in the ITT population) were comparable in the two groups (1.3% vs. 1.2%), as was admission for respiratory complications, sepsis or dehydration. Pneumonia was less common with active treatment in the ITTI population (0.5% vs. 1.6%, NNT 111), but not in the general ITT population (0.4% vs. 0.9%). The composite of otitis media, sinusitis, pneumonia and acute bronchitis (all originally considered indications for antibiotics) was less frequent with active treatment in the ITTI population (risk difference -2.8%), but not after exclusion of acute bronchitis (not typically considered an indication for antibiotics) (risk difference -0.1%). The only reported death involved a control patient in a study of patients with chronic cardiopulmonary disease.
CONCLUSIONS: The retail cost of a Tamiflu dose pack (ten 75mg capsules) is about $120. A generic formulation is not available in the USA. This review suggests that the benefit of treatment is limited. 23 references – no reprints)
Copyright 2013 by Emergency Medical Abstracts – All Rights Reserved 11/13 – #18

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In the meantime Roche has seen a windfall in the stockpiling of its drug throughout the world. Mike Leavitt, Secretary of Health and Human Services under the second Bush administration, had wanted enough treatment courses to cover a quarter of the U.S. population – about 75 million courses. In a communication from Alain Li Wan Po and colleagues from the National Genetics Education and Development Center in Birmingham, UK to the CDC it is observed that more than 70 countries are stockpiling oseltamivir and in 2003 at least 220 million treatment courses had been purchased worldwide at a cost of $6.9 billion (comes out to be about $31 per treatment course). With an estimated world population of 6.8 billion, the authors observe that on a global basis stockpiles are very inadequate.

Furthermore, observers note that “replace by” dates are approaching on some of the world’s stockpile and cash-strapped countries may have a challenge keeping up with replacement costs.

Given that current literature is fairly unenthusiastic about oseltamivir, one could challenge the expense associated with the stockpiling of oseltamivir, however, in the event of a pandemic, depending on the virus’s susceptibility, it is possible that the drug may be clinically very useful. And oseltamivir has been shown to be effective prophylaxis for influenza; not as effective as the typical annual vaccine – but then again, vaccines to new strains take months to develop and predicting next year’s predominant flu strains isn’t always perfect. Given the lack of other options, the stockpiling is defended. To help defray costs, the authors outline methods to safely increase shelf life. Given that the 1918 influenza pandemic killed 50 million people worldwide (many in developing countries) the authors stress the importance of developing effective shelf-life extension methods.

But what about the routine patient who presents to the ED with flu-like symptoms? There are a number of considerations: Many will not have the flu – particularly at edges of the annual flu season. It is unclear if oseltamivir will help these folks at all. That brings up another question – what about the flu tests? This is complicated. If knowing that a patient has the flu prevents a bunch of unnecessary blood tests, x-rays and antibiotics, they may be very defendable. If the providers were not going to do the tests and give the antibiotics in the first place then flu tests seem to be a waste of time and money (their sensitivity is variable – from 10% to 80% – but specificity is high). But if, at most, you are going to buy one day less illness with a course of $120 Tamiflu, it seems the case for the use of flu tests is pretty bleak.

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Here are two papers, one going back to 2006, discouraging routine use of oseltamivir (and this is before the new data revealing oseltamivir’s uselessness at preventing hospitalizations):

PRESCRIPTION OF ANTI-INFLUENZA DRUGS FOR HEALTHY ADULTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Burch, J., et al, Lancet Infect Dis 9:537, September 2009
BACKGROUND: These British authors point out that, in publicly funded healthcare systems, choices must be made concerning which interventions can or cannot be supported.
METHODS: The authors performed a systematic review and meta-analysis of 26 randomized controlled trials of zanamivir (Relenza) (13 trials) or oseltamivir(Tamiflu) (13 trials), commissioned by the British National Institute for Health and Clinical Excellence (NICE), to evaluate the effectiveness and cost-effectiveness of these agents as treatment for seasonal influenza in adults.
RESULTS: Among individuals with typical signs and symptoms of influenza, pooled data from placebo- controlled studies in otherwise healthy adults are consistent with a median reduction in the interval to alleviation of symptoms of 0.57 days with zanamivir (six trials) and 0.55 days with oseltamivir (four trials). In at-risk populations (e.g., children, the elderly, and patients with COPD or asthma), there was a 0.98-day decrease in the median time to alleviation of symptoms with zanamivir (seven trials); although trends favored oseltamivir in this population (six trials), there was no clear evidence of a decrease in time to resolution of symptoms with this agent. The studies provided insufficient evidence concerning the effects of active treatment on the development of influenza complications in healthy adults or in at-risk populations.
CONCLUSIONS: The authors suggest that, although “it is reasonable to recommend precautionary treatment to people who are at an increased risk of suffering influenza-related complications,” the use of antiviral drugs for patients with influenza is “unlikely to be the most appropriate course of action” given the “debatable clinical importance of their effect on symptom duration.” 62 references – no reprints)
Copyright 2010 by Emergency Medical Abstracts – All Rights Reserved 2/10 – #21

And here’s a 2014, 18-page systematic review based on clinical study reports, trial registries, electronic databases, regulatory archives and correspondence to manufacturers confirming what is generally known – no surprises but more confirmatory data.

OSELTAMIVIR FOR INFLUENZA IN ADULTS AND CHILDREN:SYSTEMATIC REVIEW OF CLINICAL STUDY REPORTS AND SUMMARY OF REGULATORY COMMENTS
Jefferson, T., et al, BMJ, April 9, 2014
Abstract Objective: To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments (“regulatory information”). Design Systematic review of regulatory information. Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. Eligibility criteria for selecting studies Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza. Main outcome measures Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population. Results From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval −0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for “pneumonia,” and no clinical study reports reported laboratory or diagnostic confirmation of “pneumonia.” The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two “pivotal” treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, −0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116). Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling

So it seems there are a bunch of reasons not to use oseltamivir in an ED patient with influenza-like illness: It costs $120 to maybe buy one day’s sooner relief (if you really have the flu and you see your clinician within one or two days of symptom onset). It’s unlikely to prevent serious complications from the flu. It is precipitating the development of resistant strains of flu. And it may be causing some funky neurologic effects in kids (at least in Japan).

With flu season upon us there will be lots of pressure to dole out lots of oseltamivir prescriptions (especially if patient expectations are created through lots of direct-to-consumer TV ads). Doctor, aren’t you going to prescribe the flu pills? So it won’t be easy, but it is worth a try. We are in the supposed age of informed decision making. Just tell the patient the contents of the prior paragraph and let them help decide. It is the fair, reasonable and ethical thing to do.

Rick Bukata, MD is the managing editor of Emergency Medical Abstracts