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expert reaction to new meta-analysis investigating effectiveness and side-effects of Tamiflu (oseltamivir) for seasonal influenza

Researchers have published in the Lancet journal a meta-analysis of the effects of Tamiflu, reporting beneficial effects on alleviation of symptoms and risk of complications, but also on an increase in side effects such as nausea. These comments were accompanied by a Before the Headlines analysis.

 

Dr Tom Jefferson, epidemiologist at the Cochrane Acute Respiratory Infections Review Group, said:

“From a transparency perspective, I was disappointed to see that the Lancet press release does not mention that the funding for this study comes from Tamiflu’s manufacturer, Roche. Roche funded MUGAS and MUGAS funded the research. See this Roche press release from 2013 http://www.roche.com/media/store/statements/med-stat-2013-02-26.htm

“On the science side, there are no new data presented here on complications or hospitalizations that we did not already know of and present and make public in April last year in our Cochrane review.  The reasons the conclusions are different is because they have differing interpretation of the same data.

“They for example are apparently happy to trust that what was recorded as “pneumonia” really was pneumonia when patients got antibiotics. I would challenge that assumption.  Our interpretations are in line with FDA, which does not allow Roche to claim Tamiflu reduces the risk of complications.  See http://www.nytimes.com/2012/04/11/opinion/drug-data-shouldnt-be-secret.html  Our interpretations were driven by our access to over 100,000 pages of Tamiflu clinical study reports, something these authors did not access according to their methods section, but something the FDA did.

“I am curious to know when the authors wrote the original protocol for this study. Was it peer-reviewed and/or published?

“Also, on page 8 the authors write, “Our results for complications and admittance to hospital are broadly consistent with those of observational studies and some previous meta-analyses of randomised trials.20,28–31”.  This is misleading. Citation 28 is to a paper by Hernan and Lipsitch which stated “it was not possible to assess the potential benefit for high-risk participants who are hospitalised, because the sample size of most studies was too small to consider hospitalisation as an outcome.”

“So this new Lancet paper and the Hernan-Lipsitch paper it cites are not “broadly consistent” on admittance to hospital; they are inconsistent, and they were looking at the same dataset.”

 

Prof. Kevin McConway, Professor of Applied Statistics, The Open University, said:

“This is a good and careful study, adding significantly to what we know scientifically about Tamiflu. But there are still open questions, particularly on exactly how and when it should be used. This new review used data from individual patients, which is generally regarded as better than basing a review on aggregated study results, as in the Cochrane review published last Spring. In very broad terms, though, the conclusions are much the same. The evidence is that Tamiflu does, on average, reduce the length of time until flu symptoms go away. That reduction is statistically significant, which means it looks like a real effect of the drug and isn’t just due to chance variation. But that doesn’t necessarily mean the reduction is large. Looking across all the patients in the trials, this new study shows an average reduction of about 18 hours, not much different from what the Cochrane review found. In patients whose diagnosis of influenza was confirmed by laboratory tests, the average reduction was greater, about 25 hours, but there remains considerable uncertainty in this estimate, and even then it is only an average and the outcome in individual patients could be a lot different.

“But is a reduction of this size worthwhile, particularly given that the new review confirmed that Tamiflu has side effects? Tamiflu increases the risk of nausea and vomiting. A study like this can’t on its own say whether it is worthwhile to trade off the reduction in the length of symptoms against the risk of nausea and vomiting. That is particularly true in relation to the possible use of Tamiflu in a future severe flu epidemic, where it would not be feasible to confirm all diagnoses in a laboratory. Making such a decision requires some complicated value judgements.”

 

Prof. Wendy Barclay, Chair in Influenza Virology, Imperial College London, said:

“The publication of the meta analysis by MUGAS confirms that neuraminidase inhibitor drugs are specific and effective in a clinical setting. It is now obvious that the balance of side effects vs benefits will play out differently in a typical winter season where influenza might only be responsible for a fraction of respiratory illness, than in a pandemic setting where nearly all cases might be caused by flu and increased severity is a real possibility.  The heated discussions that have arisen in recent times around stockpiling and use of these drugs should be countered by the question ‘what exactly do we expect for the best antiviral against influenza we could imagine?’ Could we ever do better than this, and how? As Ben Cowling quite rightly points out in his commentary that accompanies the paper, to improve our ability to use an antiviral to control an acute infection we will need to develop more sensitive and rapid diagnostic tools in order to deliver the drug to the patient earlier. It is probably this lack of diagnostic ability rather than a deficiency in the antiviral agents themselves that currently limits our efforts.”

 

Prof. Carl Heneghan, Professor of Evidence-Based Medicine and Director of the Centre for Evidence Based Medicine, University of Oxford, said:

“I have concerns with the undertaking of the Dobson paper in the Lancet: how the results are presented, the harms of treatments and the peer review, which missed important issues that should be taken into account and addressed.

“To put the Dobson results into context, if the results on hospitalisations were correct and we discounted all of the biases and the harms, then if the rate of circulating influenza in the population was 30%, (the rest was other viral infections referred to as influenza like illness) for every 1000 people treated 3 hospitalizations would be avoided.

“However, the rates of injury and poisoning were high. This finding is worrying given the dose adjustment required in the elderly with poor renal clearance: “injury and poisoning RR 3·37 (95% CI 1·08 to 10·47) P=0·036.” (see table 2 in the paper).

“The result also inform us that there is no benefit of using oseltamivir in the elderly, given there was no symptom relieving effect in this age group (over 65 years).

“The time ratio of oseltamivir versus placebo recipients was attenuated for high-risk participants (≥65 years or in chronic illness trial or chronic obstructive airways disease at baseline).” (See Figure 3 in the paper)

“The main complication reported was lower respiratory tract complication more than 48 hours after randomisation requiring antibiotics. However, the Dobson paper confirms that the diagnosis of pneumonia was not based on a valid measure: “participant report and the investigator’s clinical judgment” and not on objective measure such as x-ray. Why these lack of definitions were not originally reported in the earlier papers is a major issue that has led to confusion amongst those who make clinical decisions. But, the Dobson paper confirms there is no evidence that oseltamivir reduces pneumonia.

“The use of lower respiratory tract complications requiring antibiotics is not a clinically relevant outcome. Much of the reported effect on this outcome is driven by bronchitis, a condition for which antibiotics are not indicated, and acute bronchitis is often an indicator of respiratory syncytial virus (RSV) not influenza. We know from the results of a Cochrane “systematic review “There is limited evidence to support the use of antibiotics in acute bronchitis.’ (See box 1, below)

“Furthermore, the Dobson paper used the same outcome as the Hernan study [2] of “oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms.” This is puzzling as peer review should have picked up on the similarities of the analysis and that there was nothing new in this current paper, apart from one important deviation by Dobson, of only reporting complications beyond 48 hours, meaning the study had deviated from the important principle of intention to treat (see box 2, below).

“As opposed to the 20 trials included in the Cochrane systematic review, this current analysis included only 9 treatment trials and crucially did not perform a quality assessment of the evidence, and as such, the Roche funded study  published in the Lancet doesn’t meet the criteria for a systematic review. In addition, unlike Cochrane systematic reviews, there was no protocol pre-specified at the outset, which the authors should not deviate from, or if they do should be explained.

“The Dobson review analysed the infected group of patients separately, despite the fact our previous review had clearly discovered compelling evidence that this population (the intention to treat influenza infected population) deemed to be influenza infected was not balanced between treatment groups in the oseltamivir trials. Furthermore results from the whole population (intention to treat population) are of use to clinical practice because routine testing for influenza is not used and is impractical.

“I am unsure how the definition of 21.5 hours has been arrived at. Why not 22 or 23 hours? However, this symptomatic reduction is not new and adds little to what we already know. A more informative outcome, given the investigators had the IPD data would have been an analysis of those on and off rescue treatment (i.e. those taking paracetamol or not). There should be no reason why this analysis cannot and should not be done.

“From the Cochrane review results for the treatment of adults [3] there was no difference in rates of admission to hospital between treatment groups (38/2663 in the hospital arm versus 32/1731 in the placebo arm). Dobson splits the results into the infected group, which is misleading as multiple subgroup results often leads to spurious findings. Even presenting this best-case scenario the absolute effect is small (1%) for those with influenza and non-existent for those with influenza like illness.

“In 2014 in the Annals of Internal Medicine, 7 out of 8 studies involving researchers with financial conflicts of interest came to positive conclusions about the effectiveness of neuraminidase inhibitors. But, only 5 of the 29 studies conducted by scientists who did not receive money had favorable outcomes. [4] It is time we took seriously the effects conflicts of interest have upon the reporting of clinical findings and looked purely beyond the spin to the important outcomes that make a difference to patients.”

  1. Antibiotics for acute bronchitis.Smith SM, Fahey T, Smucny J, Becker LA.Cochrane Database Syst Rev. 2014 Mar 1;3:CD000245. doi: 10.1002/14651858.CD000245.pub3. Review.
  1. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Hernán MA, Lipsitch M. Clin Infect Dis. 2011 Aug 1;53(3):277-9. doi: 10.1093/cid/cir400. Epub 2011 Jun 15.
  1. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. BMJ. 2014 Apr 9;348:g2545. doi: 10.1136/bmj.g2545. Review.
  1. Financial conflicts of interest and conclusions about neuraminidase inhibitors for influenza: an analysis of systematic reviews. Dunn AG, Arachi D, Hudgins J, Tsafnat G, Coiera E, Bourgeois FT. Ann Intern Med. 2014 Oct 7;161(7):513-8. doi: 10.7326/M14-0933.
Box 1: Antibiotics for acute bronchitis. Smith SM, Fahey T, Smucny J, Becker LA. Cochrane Database Syst Rev. 2014 Mar 1;3:CD000245. [1]Conclusions “There is limited evidence to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest beneficial effect in some patients such as frail, elderly people with multimorbidity who may not have been included in trials to date. However, the magnitude of this benefit needs to be considered in the broader context of potential side effects, medicalisation for a self-limiting condition, increased resistance to respiratory pathogens and cost of antibiotic treatment.”
Box 2: Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Hernán MA, Lipsitch M. Clin Infect Dis. 2011 Aug 1;53(3):277-9. [2]Hernan methods: “Second, we included endpoints diagnosed during the first 2 days after randomization. These events were excluded by Kaiser et al [1] because they hypothesized that oseltamivir could have no effect during the first 2 days. Although reasonable, this approach deviates from the intention-to-treat principle used in many randomized trials, in which investigators refrain from making assumptions about the timing of effects and thus include all events after randomization in the analysis.”

 

Prof. Peter Openshaw, Director of the Centre for Respiratory Infection, Imperial College London, said:

“The important thing about this study is that it shows that Roche were not hiding skeletons in its cupboards. As a full review of the published and unpublished data, it leaves the conclusion unaltered that oseltamivir reduces symptom duration by about a day while causing nausea and vomiting in a minority of recipients.

“Oseltamivir is not a perfect drug but does what you might expect of an antiviral given relatively late in the course of an acute infection and after the illness has already become established. The finding that it reduces hospitalisation by 63% is especially important, reinforcing the call for family practitioners to use antivirals early rather than resorting to antibiotics, which are of no proven benefit in uncomplicated flu.”

 

Dr John McCauley, Director of the WHO Collaborating Centre for Influenza, MRC National Institute for Medical Research (NIMR), said:

“The impact of influenza can be mitigated by vaccination or through the use of antiviral medicines. When a new pandemic influenza virus emerges it is likely that antiviral medicines will be the main weapon to combat the disease until vaccines are prepared. In years where the influenza vaccine might be sub-optimal, for example in years when a new antigenic variant emerges, again the use of antiviral medicines will have an important role to play in reducing influenza illness.

“There have been many questions about the effectiveness of oseltamivir for the control of influenza. For example, observational studies reported in 2013 and 2014 from a world-wide collaboration integration of results from many centres, indicated that rapid initiation of the use of oseltamivir was beneficial in controlling severe influenza. However, clinical trials are deemed superior to observation studies due to possible unintended biases influencing observational studies. The current work by Dobson, Whitely, Pocock and Monto has re-examined the results from previous clinical trials on the effectiveness of oseltamivir and were able to include more data than had been previously analysed. The authors of the current study concluded that oseltamivir treatment resulted in shorter periods of illness, and moreover, because of the ability to put together the results from many trails, the authors concluded that influenza patients treated with oseltamivir had a reduced risk of being hospitalized or having antibiotics prescribed for lower respiratory tract infection. However, the authors also noted that treatment with oseltamivir induced an increased rate of reporting nausea, and pointed out that the risks and benefits of oseltamivir use still need to be considered carefully.”

 

‘Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials’ by Joanna Dobson et al. published in the Lancet on Friday 30 January 2015. 

 

Declared interests

Prof Carl Heneghan is a co-recipient of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children—http://www.nets.nihr.ac.uk/projects/hta/108001).

Prof Peter Openshaw’s research is funded by the Wellcome Trust, the MRC, BBSRC and the European Union. He has received honoraria or consultancy fees from GSK, Janssen, Johnston and Johnston and Sanofi.

Dr John McCauley is Director of the WHO Collaborating Centre for Reference and Research at the MRC National Institute for Medical Research. His work is funded by the Medical Research Council.

 

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