Just over two years ago in The Tamiflu Controversy Continues, we looked at the ongoing debate over the effectiveness of oseltamivir (Tamiflu ®) in the wake of the release of a Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission.
February 7, 2012 -- A recent review of randomized clinical trial data for the influenza neuraminidase inhibitor antiviral medications published by the Cochrane Collaboration, and two related commentaries [“Rethinking credible evidence synthesis” and “Questions Remain over safety and effectiveness of oseltamivir”] published in the British Medical Journal, raised questions about the value of antiviral medications for the prevention and treatment of influenza. After careful consideration of all available evidence, CDC guidance on the use of antiviral medications remains unchanged. The Centers for Disease Control and Prevention (CDC) continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct in the prevention and treatment of influenza.
Since then the CDC and the World Health Organization have continued to promote Oseltamivir and other NAI antivirals as important drugs in our limited arsenal against the influenza virus (see November 2013 CDC Research On Benefits Of Antivirals For Uncomplicated Influenza).
Yesterday the BMJ and the Cochrane Group published a new assessment of the antiviral drug Tamiflu, and as they have in the past, cast doubts on its efficacy and on the wisdom of governments around the world stockpiling the drug.
The entire study is available online. You’ll find the link and a small excerpt below:
BMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2545 (Published 10 April 2014)
Cite this as: BMJ 2014;348:g2545Tom Jefferson, reviewer, Mark Jones, senior research fellow (biostatistics), Peter Doshi, assistant professor, Elizabeth A Spencer, nutritional epidemiologist, Igho Onakpoya, research fellow in evidence-based practice and pharmacovigilance, Carl J Heneghan, professor
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.
The Cochrane Summary is available at:
Editorial Group: Cochrane Acute Respiratory Infections Group
Published Online: 10 APR 2014
While research purists may applaud their methods, the problem that I (and many others) have with this analysis is that the Cochrane group set the bar very high as to what studies they would consider, excluding many observational studies.
Randomized controlled trials (RCTs) are considered the `gold standard’ for drug research, but these types of studies are expensive and notoriously difficult to conduct ethically when trying to evaluate a potentially life saving drug.
Overnight some elements of the British press have morphed their findings into incendiary headlines, such as this one from the Daily Mail: Ministers blew £650MILLION on useless anti-flu drugs.
Much of this ire has been well-earned through Roche’s long-standing resistance to releasing all of the testing data on their antiviral drug, and that has led to critical editorials in the BMJ, and frequent excoriation in the British press.
For a different perspective, we turn to NBC’s Senior health writer Maggie Fox, who spoke to doctors whose job it is to treat patients with influenza.
By Maggie Fox
A team of researchers who have been studying the flu drugs Tamiflu and Relenza released a new report that they say raises new doubts about the benefits of the drugs. But flu experts lined up to defend the medications, which they say can help reduce the most severe and deadly effects of the virus.
The report, published jointly by the influential Cochrane Review and the British Medical Journal, seeks to cast doubt on the widespread use of the two drugs, which doctors give to treat influenza and to prevent it in people who have a high risk of complications.
Despite its critics, there are studies that show that Tamiflu can significantly reduce morbidity and mortality associated with influenza – particularly with severe, or novel infections. Some we’ve looked at in the past include:
- In 2010 we saw an observational study that appeared in JAMA (see Study: Antivirals Saved Lives Of Pregnant Women) that strongly suggested that Tamiflu was life saving for some patients with pandemic flu.
- And again in 2010, in BMJ: Efficacy of Oseltamivir In Mild H1N1, we saw a study which suggested that the administration of oseltamivir may have significantly reduced the incidence of pneumonia among otherwise healthy pandemic H1N1 patients.
- In December of 2012, in Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic we looked at a meta-analysis of 90 observational studies that appeared in the Journal of Infectious Diseases that spanned nearly 35,000 patients, 85% of whom has laboratory confirmed H1N1.
Their main finding was antiviral therapy - principally oseltamivir - initiated within 48 hours of onset, reduced the likelihood of severe outcomes, namely admission to a critical care unit or death, by 49 to 65%.
- Last month in The Lancet: Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases we looked at yet another observational study conducted by researchers at The University of Nottingham – that reviewed more than 29,000 hospitalized H1N1pdm cases across 38 countries between 2009 and 2011, and found that the administration of NAI antivirals was associated with a 19% reduction in mortality compared to receiving no NAI treatment at all.
And finally, for those who question the value of Tamiflu in novel flu pandemic, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on outcomes of H5N1 patients who either received, or did not receive, antiviral treatment. The research appears in the IDSA’s Journal of Infectious Diseases. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.
But . . . of those who received at least one dose of Tamiflu . . . 60% survived . . . as opposed to only 24% who received no antivirals.
While we would all prefer to have rock-solid, indisputable evidence based on well-mounted RCTs proving the effectiveness of Oseltamivir, the preponderance of evidence we have today still indicates that NAIs can have a substantial positive therapeutic effect on influenza, particularly in high risk patients or with novel flu strains.
Besides, unless and until better therapeutic options become available, they pretty much the only game in town.