GP authors of the Cochrane review on antivirals for flu have written to NICE urging them to carry out an urgent review of guidelines because of concerns the drugs could be causing more harm than good, Pulse has learned.
In a letter sent to NICE chair Professor David Haslam this month, the researchers urged NICE to reconsider evidence from their Cochrane review published last year showing neither oseltamivir (Tamiflu) nor zanamivir (Relenza) reduce complications or hospitalisations from flu, and raising new concerns over side effects.
The move came as it emerged GP leaders had received complaints from practices that public health officials were pushing them to prescribe Tamiflu to large numbers of care home residents as a preventative measure, with some developing apparent side effects of the treatment.
Co-author of the Cochrane review Professor Carl Heneghan, professor of evidence-based medicine at the University of Oxford and a practicing GP, told Pulse that he and lead author, Professor Tom Jefferson, a former GP and member of the Cochrane Review Group, were ‘perplexed’ that NICE was continuing to recommend use of antivirals for either treatment or prophylaxis.
He said: ‘We were perplexed. [We] have written a letter to David Haslam at NICE, asking them to clarify the situation because we can’t understand how they can give guidance if they are not prepared to look at the whole evidence base.’
Professor Heneghan added that the researchers were also very concerned to learn from GP leaders that PHE was continuing to advise prescription of Tamiflu, particularly for prevention in elderly nursing home patients, a setting in which their evidence had found the drugs do not offer any benefits and may cause harms.
Professor Heneghan said: ‘I cannot understand why [they have advised this]. I may write to PHE to ask, where is the evidence for what they are doing?
‘In a nursing home, there is no evidence there is any benefit – in fact the evidence is it causes harm.’
The gold standard Cochrane review, published in April last year, analysed previously withheld trial data and regulatory reports, and found Tamiflu and Relenza shortened the duration of symptoms, but failed to reduce complications or hospitalisations in people with seasonal flu, or prevent transmission of flu – while they increased the risk of side effects, including neuropsychiatric, gastrointestinal and renal events.
The review included two randomised trials – WV15708 and WV15825 – that looked specifically at prophylaxis in elderly patients in nursing homes, neither of which found a statistically significant benefit in terms of reducing cases of either symptomatic or asymptomatic flu, or complications or hospitalisations, but showed increases in gastrointestinal and neuropsychiatric side effects.
NICE decided last summer not to review and update its guidelines on antivirals for treatment and prophylaxis, however, arguing its guidance is aimed at use in high-risk patients whereas the latest Cochrane findings were not available for these subgroups, while smaller effects on symptoms than had previously been reported were unlikely to change its cost-effectiveness estimates.
In addition, it said the new finding of an increase in neuropsychiatric events was limited to ‘healthy people’, and should be investigated by drugs regulators.
NICE said: ‘Although this is important new data, and potentially could be relevant to be considered in a technology appraisal, we consider it first and foremost something for the regulators to look at.’
Public Health England (PHE) also backed use of the antiviral drugs for seasonal flu this winter, in line with the NICE guidelines, and emphasised the drugs should be used in ‘severely unwell patients’ as a recent meta-analysis of observational data – excluded from the Cochrane review – had shown they could reduce the risk of death in patients hospitalised with flu.
However, in their letter to NICE, Professor Heneghan and Professor Jefferson noted that ‘even in individuals at higher risk of complications, such as children with asthma or the elderly, we found no evidence of a beneficial effect for reducing risks of complications’, and that NICE’s position ‘is incompatible with evidence-based guidance’, ‘particularly if it is not prepared to look at the benefit to risk ratio of the drug… and is otherwise to rely on expert opinion and economic models that are not based on the transparent evidence base’.
NICE confirmed to Pulse it has acknowledged the letter and will respond in due course, but declined to comment further.
PHE defended its advice, saying the evidence in support of antivirals ‘was clear’.
In a statement to Pulse, Professor Paul Cosford, director for health protection and medical director at PHE, said: ‘The severe impact that flu can have on the health of people at risk in our communities and on our health services is unquestionable and the evidence to support the appropriate use of antivirals when flu is circulating is clear.
‘When prescribed appropriately, they can reduce the risk of death in patients hospitalised with flu or in those at greater risk from the complications of the virus – and this often includes elderly residents in care homes where mortality during outbreaks is often substantial.’
Professor Cosford added: ‘It is concerning that doctors may be deterred from prescribing antivirals and ultimately this could be putting lives at risk. Many studies and reviews, including the recent Cochrane review, have concluded that the antiviral drugs oseltamivir and zanamivir, when used for post-exposure prophylaxis, are effective in preventing the occurrence of secondary cases of symptomatic influenza.’
Roche, the manufacturer of Tamiflu, issued the following statement: ‘Roche cannot comment on NHS policy. However, Roche supports the use of Tamiflu as a NICE recommended medicine for the treatment and prevention of flu.
‘Both clinical trials (with Tamiflu compared to placebo) and real-world data from seasonal influenza and the 2009-2010 flu pandemic have shown that Tamiflu is effective in reducing the severity and duration of symptoms in those infected with flu, and a recent study of patient-level data from nearly 30,000 patients in a pandemic setting, published in The Lancet Respiratory Medicine, also showed that treatment with Tamiflu was associated with a reduction in the risk of death when compared with no treatment.
‘The side effects of Tamiflu are well-documented and well-understood from 15 years of patient experience and from having been taken by over 130 million people worldwide. For their analysis, Cochrane only used 15 of the 77 CSRs that Roche provided. Roche believes that in order to properly make a safety assessment, all data must be evaluated including all relevant CSRs, published literature and spontaneous safety reports.’
GSK, which manufactures Relenza, had not commented at the time of publication.