Have you read the revised Cochrane Review regarding neuraminidase inhibitors for preventing and treating influenza? If you have, I’m impressed; it’s 559 pages long. There are almost 250 pages of outcomes and treatment comparisons. It is serious business.
And, it needs to be – because these folks from the Cochrane Collaboration are going up against Roche and a spin machine supporting of billions of dollars in revenue and pandemic flu strategic stockpiling. The question: do oseltamivir and zanamivir provide symptomatic relief and prevent serious complications from influenza infection with a reasonable safety margin?
Covering 20 oseltamivir (9,623 participants) and 26 zanamivir (14,628 participants) trials under a new data-sharing agreement, these authors ultimately conclude any faith in neuraminidase inhibitors is unwarranted. Each treatment provided an advantage of less than a day with regard to symptom resolution – reducing the average duration of symptoms from nearly 7 days to slightly over 6 days. Neither treatment had any effect on hospitalizations. Pneumonia definitions were not standardized across trials; a 1% relative risk reduction was seen in investigator-reported pneumonia, but no reduction was seen in studies with radiologic objective measures of pneumonia. Importantly, both neuraminidase inhibitors – osletamivir especially – were associated with adverse effects. Nausea & vomiting were the most prominent symptoms, but neuropsychiatric disturbances were increased in a dose-dependent fashion.
Even more damning, there was universal risk of bias across trials – particularly for osletamivir. The quality of the outcome follow-up for post-treatment complications was poor, allocation was not always blinded, and there was evidence of selective reporting of results. That any government or guideline organization would base massive public health expenditures on a pharmaceutical corporation’s incomplete reporting of low-quality trials is simply indefensible.
So, there is a small, debatably unimportant effect on symptom duration. There is zero evidence supporting the routine use of these agents to reduce subsequent infection. This evidence does not exclude an important effect in a selected sub-population, but the authors of this review feel the underlying mechanism of action does not support such use until an effect is verified. Furthermore, with regard to follow-up trials, the overall incidence of bacterial complications from influenza is low enough a sample size of over 20,000 patients would be required to detect a clinically meaningful difference.
It must be said – there is likewise potential bias on the side of these authors, who have long been vilifying Roche in this battle over open drug data. The next step, we hope, will be opening the data to all to review and verify their findings. We can hope, through repeated battles such as this, the open data day will come where we are able to properly protect patients from inadequate trial evidence.
In the meantime – let us purge ourselves of mandates and patient expectations for Tamiflu before the next influenza season rears its ugly head.
“Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children”