Effectiveness of Tamiflu and Relenza questioned

“Ministers blew £650 MILLION on useless anti-flu drugs,” the Daily Mail reports. The paper cites a large study, which investigated the effectiveness of the antiviral drugs Tamiflu (oseltamivir) and Relenza (zanamivir).

These drugs, called neuraminidase inhibitors, have been stockpiled in many countries, including the UK, to prevent and treat large influenza outbreaks.

The systematic review by the Cochrane Collaboration covered the benefits and damage of the drugs in both adults and children. It took into account new data that had previously been kept confidential by the drugs’ manufacturers: Roche (which manufactures Tamiflu) and GlaxoSmithKline (GSK) (which manufactures Relenza).

It found that both drugs shorten the symptoms of influenza-like illness by about half a day in adults (but not in asthmatic children), compared to a placebo. There was no reliable evidence that either drug reduces the risk of people with flu being admitted to hospital or developing serious complications such as pneumonia, bronchitis, sinusitis or ear infection. Used as a preventative measure, Tamiflu and Relenza slightly reduced the risk of developing the symptoms of flu. The review also found no evidence that these drugs can stop people carrying the influenza virus and spreading it to others.

The study also found that Tamiflu slightly increases the risk of adverse effects such as nausea, vomiting, psychiatric and kidney problems in adults, and vomiting in children.

This is an important, well-conducted review of a controversial topic. Most experts would agree that the modest benefits of Tamiflu and Relenza, as reported by the review, do not justify the increased adverse risks, let alone the money spent on them by the UK.

Where did the story come from?

The study was carried out by researchers from the Cochrane Collaboration – an independent, international research network that produces rigorous systematic reviews on healthcare interventions. There was no external funding. The study was published in the peer-reviewed Cochrane Database of Systematic Reviews, which is an open access journal, meaning the study is free to read online.

The review was widely covered by the media, with many reports taking information straight from an accompanying press release. However, most papers also included comments from independent experts, the Department of Health and the two drug companies (GSK and Roche).

What kind of research was this?

This was a systematic review that aimed to assess the potential benefits and harms of oseltamivir and zanamivir (known as neuraminidase inhibitors) in the prevention and treatment of influenza in healthy adults and children.

The researchers explain that previous reviews of the drugs have been hampered by “unresolved discrepancies” in the data from published trials, as well as problems with publication bias.

Previously, concerns about the effectiveness of Tamiflu have been raised, with data suggesting it was not as effective as previously thought not released for external peer review and scrutiny.

They therefore did not use the data directly from journal articles, but went to unpublished documents from both regulatory bodies and the manufacturers.

The researchers point out that oseltamivir and zanamivir have been stockpiled in many countries to prevent and treat both seasonal and pandemic influenza, and are now used worldwide. In particular, the worldwide use of Tamiflu has increased dramatically since the outbreak of swine flu in April 2009. It was initially believed that the drug would reduce hospital admissions and complications of influenza, such as pneumonia, during influenza pandemics.

What did the research involve?

The researchers searched trial registries, electronic databases (up to July 22 2013) and regulatory archives, and corresponded with manufacturers to identify all relevant, randomised controlled trials (RCTs) with placebos. They also requested the unpublished reports on which the trials were based.

They made sure there were no published RCTs from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. They found that all RCTs were sponsored by the manufacturers.

Once the data from clinical study reports was collected, they assessed the risk of bias in the published trials. They analysed the effects of zanamivir and oseltamivir on:

The duration of symptoms
Influenza outcomes
Complications
Admissions to hospital
Adverse events

What were the basic results?

The researchers obtained 107 study reports from drug regulatory bodies and drug manufacturers. They eventually used data from 46 trials – 20 on oseltamivir, with 9623 participants; and 26 on zanamivir, with 14,628 participants. They identified problems with the design of many of the trials included, which they say affects confidence in the results.

Here are the main findings from the review:

Reduction in the duration of symptoms

In adults, oseltamivir reduced the time it took to first alleviate symptoms by 16.8 hours (95% confidence interval [CI] 8.4 to 25.1 hours). This represents a reduction in the duration of symptoms from 7.0 to 6.3 days.
There was no effect in asthmatic children – but in otherwise healthy children, there was an average reduction in the time it took to first alleviate symptoms of 29 hours (95% CI 12 to 47 hours).
In adults, zanamivir reduced the time until the first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81). This represents a reduction in the average duration of symptoms from 6.6 to 6.0 days. The effect in children was not statistically significant.

Admission to hospital

In both adults and children, treatment with oseltamivir had no significant effect on whether they were admitted to hospital (risk difference (RD) 0.15% (95% CI -0.78 to 0.91).
Data on admission to hospital and zanamivir was unreported.

Serious influenza complications

In both adults and children treated with oseltamivir, the drug did not significantly reduce serious complications or those that led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44).
In adults either treated with zanamivir or taking it for prevention, the drug did not reduce complications.

There was insufficient evidence to say whether oseltamivir used for prevention or zanamivir used for treatment reduced complications in children.

Pneumonia

The evidence on the effects of either drug used in treatment or prevention of pneumonia risk was deemed unreliable.

Bronchitis, sinusitis and middle ear infection

In adults treated with zanamivir, the drug significantly reduced the risk of bronchitis (RD 1.80%, 95% CI 0.65 to 2.80), but oseltamivir did not. Neither drug significantly reduced the risk of middle ear infection or sinusitis in either adults or children.

Harms of treatment

Adults treated with oseltamivir had an increased risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); and vomiting (RD 4.56%, 95% CI 2.39 to 7.58).
Adults treated with oseltamivir had significantly lower increases in the numbers of antibodies (needed by the body to fight infection) compared to the control group (RR 0.92, 95% CI 0.86 to 0.97)
Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0), compared to a placebo
two treatment trials with oseltamivir showed a “dose response” effect on psychiatric events (such as feelings of nervousness or aggression)
Children treated with oseltamivir had a higher risk of vomiting (RD 5.34%, 95% CI 1.75 to 10.29). Children on oseltamivir also had a lower increase in the number of antibodies (RR 0.90, 95% CI 0.80 to 1.00).

Prevention

Used for prevention, oseltamivir and zanamivir reduced the risk of flu symptoms in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88)), (zanamivir: RD 1.98% (95% CI 0.98 to 2.54)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47)), (zanamivir: RD 14.84% (95% CI 12.18 to 16.55))
Oseltamivir increased the risk of psychiatric adverse events (RD 1.06%, 95% CI 0.07 to 2.76); headaches (RD 3.15%, 95% CI 0.88 to 5.78), kidney problems (RD 0.67%, 95% CI -2.93 to 0.01) and nausea (RD 4.15%, 95% CI 0.86 to 9.51)

How did the researchers interpret the results?

The researchers say that on the the basis of their findings, clinicians and healthcare policy-makers should “urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza”. They say “it is unclear whether this is superior to treatment with commonly used antipyretic medications [paracetamol]”. They go on to say they “did not find any credible evidence that either oseltamivir or zanamivir reduce the risk of complications of influenza, particularly pneumonia, nor reduce risk of hospitalisation or death. Moreover, even in individuals with a 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”.

It is of “some concern” they say that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher-risk groups with influenza.

In an accompanying press release, Dr Tom Jefferson, Dr Carl Heneghan and Dr Peter Doshi, authors of the review, said: “Drug approval and use cannot be based on biased or missing information any longer. We risk too much in our population’s health and economy. This updated Cochrane review is the first time a Cochrane systematic review has been based only on clinical study reports and regulator’s comments. It is the first example of open science in medicine using full clinical study reports available without conditions. Therefore, the conclusions are that much richer. We urge people not to trust in published trials alone or on comment from conflicted health decision makers, but to view the information for themselves.”

Conclusion

This major review is particularly significant for its use of unpublished, previously confidential data from both the drug manufacturers and regulators, to verify the information in published trials. As the researchers point out, much of the trial data is unreliable for various reasons, which makes it difficult to draw firm conclusions.

While it appears that these drugs have a modest benefit, there is no solid evidence that either drug can protect people from the more serious complications of influenza.

Paracetamol or ibuprofen would seem to be a far more cost-effective method of relieving the symptoms of influenza.