Tamiflu reduces complications of flu, new review findsBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h537 (Published 30 January 2015) Cite this as: BMJ 2015;350:h537
A new analysis of oseltamivir (marketed as Tamiflu) has found that the antiviral drug shortens the duration of symptoms of flu by about a day and reduces the risk of complications, such as pneumonia, and admissions to hospital of patients with confirmed flu.
The analysis, published in the Lancet, was led by Arnold Monto, professor of epidemiology at the University of Michigan School of Public Health, and Stuart Pocock, professor of medical statistics at the London School of Hygiene and Tropical Medicine. It was funded by the Multiparty Group for Advice on Science (MUGAS) Foundation through an unrestricted grant by oseltamivir’s manufacturer, Roche.1 The effectiveness of neuraminidase inhibitors such as oseltamivir has been much debated in recent years, especially as many governments have spent many millions of pounds on stockpiling the drugs in preparation for a flu pandemic. For example, England’s Department of Health spent £560m (€750m; $850m) on antivirals between 2006-07 and 2012-13, but MPs and the National Audit Office, which scrutinises public spending, have questioned this use of taxpayers’ money because of uncertainty over the drugs’ effectiveness.2
For the Lancet analysis, researchers used data on individual patients from nine trials sponsored by Roche, six of which were published and three of which were unpublished, involving 4328 adults who were treated for flu symptoms with 75 mg oseltamivir or placebo between 1997 and 2001. They found that, overall, the duration of symptoms was less in adults with laboratory confirmed flu who were treated with oseltamivir than in those who received placebo (97.5 versus 122.7 hours; difference 25.2 (95% confidence interval to 16.0 to 36.2)). In the 2402 participants in the intention to treat trials, the difference in duration was 17.8 hours (9.3 to 17.0).
This finding is similar to that from a systematic review by Cochrane researchers published in The BMJ last year, which found that oseltamivir shortened the duration of symptoms in adults by 16.8 hours (8.4 to 25.1; P<0.0001).3 This review was based on clinical study reports released by Roche after four and a half years of requests for the data by the reviewers and The BMJ.
In terms of complications the Lancet analysis found that fewer people treated with oseltamivir needed treatment with antibiotics than those in the placebo group (relative risk 0.56 (0.42 to 0.75; P=0.0001)), although the rates of complications were low. In the intention to treat studies 56 people given oseltamivir (3.6%) and 87 in the placebo group (6.9%) developed bronchitis; nine taking oseltamivir (0.6%) and 21 on placebo (1.7%) were treated for pneumonia, and one taking oseltamivir (0.1%) and four on placebo (0.3%) were treated for a lower respiratory tract infection.
Fewer trial participants with confirmed flu who were treated with oseltamivir (nine of 1591 (0.6%)) than in the placebo group (22 of 1302 (1.7%)) were admitted to hospital for any cause (risk reduction 0.63 (0.17 to 0.81; P=0.013). But when the researchers included all of the intention to treat participants in this part of the analysis, including those with unconfirmed flu, they found that the number of patients admitted to hospital did not differ between the oseltamivir group (25 of 2402 (0.1%)) and the placebo group (35 of 1926 (0.1%)) (risk reduction 0.61 (0.36 to 1.03; P=0.066)).
This finding in people with confirmed flu contrasts with that of the Cochrane reviewers, who found no good evidence that oseltamivir reduced the number of people admitted to hospital or that it reduced complications of flu.3 A review by the US Food and Drug Administration also found no evidence that oseltamivir prevented complications.4
In terms of side effects the Lancet analysis found that, compared with the placebo group, the incidence of nausea was higher in the oseltamivir group (absolute increase 3.7%), as was the incidence of vomiting (4.7%). These increases were similar to that seen by the Cochrane reviewers (increase of 4%), with about one in 10 patients affected by these side effects.
Monto said that the analysis provided “compelling evidence” that oseltamivir reduced duration of symptoms, complications, and hospital admissions. But he added, “Whether the magnitude of these benefits outweighs the harms of nausea and vomiting needs careful consideration.”
In an email to The BMJ the Cochrane reviewers said, “These findings differ from those from our own analysis of clinical study reports and the analysis conducted by the FDA using the same data as Dobson et al [the new Lancet review]. Neither the FDA nor we found that oseltamivir reduced complications of influenza or hospital admissions.
“It is difficult to understand how the reviewers arrived at their findings, because they have not documented their methodology. We have no idea what the protocol is for this meta-analysis. And the authors have not fully disclosed their conflicts of interest or why a quality assessment of the studies was not carried out. It looks as if a systematic review was not carried out, only a meta-analysis of IPD [individual patient data]. This is a pointer to likely bias. We know anyway that industry funded studies of neuraminidase inhibitors provide a rosy picture—this is no exception.”
In a related commentary Heath Kelly, of the Australian National University in Canberra, and Benjamin Cowling, of the University of Hong Kong, said, “The rational use of oseltamivir is becoming clear . . . Because benefits accrue only to patients with laboratory confirmed influenza, but the risk of adverse events is increased in all patients, rapid diagnostic testing, if available, is advisable before oseltamivir administration in routine clinical practice.”5
They added, “In a pandemic or severe epidemic, oseltamivir can be used presumptively when there is a high probability that influenza-like illness is caused by influenza virus infection and when the outcome of infection is likely to be severe, but a proven strategy for rapid distribution needs to accompany any plan that proposes widespread use of oseltamivir.”
Cite this as: BMJ 2015;350:h537