Tamiflu Risks Outweigh Benefits in Children

Byron's Comments:

Bucking the public health herd-oriented proclamations of the public health machine, whether in England or America, is never easy to do.

Study Title:

Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials.

Study Abstract:

Objective To assess the effects of the neuraminidase inhibitors oseltamivir and zanamivir in treatment of children with seasonal influenza and prevention of transmission to children in households.
Design Systematic review and meta-analysis of data from published and unpublished randomised controlled trials.

Data sources Medline and Embase to June 2009, trial registries, and manufacturers and authors of relevant studies.

Review methods Eligible studies were randomised controlled trials of neuraminidase inhibitors in children aged 12 in the community (that is, not admitted to hospital) with confirmed or clinically suspected influenza. Primary outcome measures were time to resolution of illness and incidence of influenza in children living in households with index cases of influenza.

Results We identified four randomised trials of treatment of influenza (two with oseltamivir, two with zanamivir) involving 1766 children (1243 with confirmed influenza, of whom 55-69% had influenza A), and three randomised trials for postexposure prophylaxis (one with oseltamivir, two with zanamivir) involving 863 children; none of these trials tested efficacy with the current pandemic strain. Treatment trials showed reductions in median time to resolution of symptoms or return to normal activities, or both, of 0.5-1.5 days, which were significant in only two trials. A 10 day course of postexposure prophylaxis with zanamivir or oseltamivir resulted in an 8% (95% confidence interval 5% to 12%) decrease in the incidence of symptomatic influenza. Based on only one trial, oseltamivir did not reduce asthma exacerbations or improve peak flow in children with asthma. Treatment was not associated with reduction in overall use of antibiotics (risk difference –0.30, –0.13 to 0.01). Zanamivir was well tolerated, but oseltamivir was associated with an increased risk of vomiting (0.05, 0.02 to 0.09, number needed to harm=20).

Conclusions Neuraminidase inhibitors provide a small benefit by shortening the duration of illness in children with seasonal influenza and reducing household transmission. They have little effect on asthma exacerbations or the use of antibiotics. Their effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.

From press release:

LONDON, England (CNN)—Treating flu-stricken children with anti-viral medication including Tamiflu and Relenza could do more harm than good, a new report has warned.

Researchers from the University of Oxford found that while the anti-virals reduced the duration of illness by up to one day and a half, they had “little or no effect” on the likelihood of the children developing complications.

The researchers conceded that they didn’t know the extent to which their report applied to the current swine flu pandemic, but said, “based on current evidence, the effects of anti-virals on reducing the course of illness or preventing complications might be limited.”

In compiling their report, published in the British Medical Journal, the Oxford University researchers searched the world for trials of Tamiflu and Relenza on children under 12. They found seven in total; four relating to flu treatment, and three to prevention.

They say none offered a big enough study to determine whether anti-virals have any effect on the chances of children developing serious flu-related complications.

“We’ve got very little data to go on. These drugs have been used on tens of thousands, in fact millions of children worldwide, and we’ve found only four trials of treatments involving less than two thousand children,” said the report’s author, Dr Matthew Thompson, a senior clinical scientist at the Department of Primary Health Care, the University of Oxford.

“We didn’t find any trials of children under one. And none of the trials was big enough to show if there’s any effect on serious complications like pneumonia or being hospitalized,” he said.

The report found that while anti-virals reduced the duration of flu in children, they had little or no impact on the likelihood of the child developing ear infections or any other condition that may require antibiotics.

A review of one study into the effect of anti-virals on asthmatic children, who are considered to have a higher risk of developing complications from the flu virus, found that they did not reduce the risk of the asthma attacks.

The report said that one in 20 children who take Tamiflu suffer nausea and vomiting, as indicated in warnings from the drug’s manufacturer. “That obviously can be a particular problem in young children and infants where getting dehydrated is a complication of influenza,” Thompson said.

The three studies that focused on the use of anti-virals to prevent influenza taking hold, showed that their potential to stop the spread of flu was “fairly small.”

“We’d need to treat 13 children with the preventive course of one of these drugs to prevent one of them from getting flu,” Thompson said.

The report’s authors suggested governments were too quick to recommend anti-virals as the first defense against the spread of swine flu. In the United Kingdom, people who suspect they have the virus are urged to phone a government helpline. If enough symptoms match the operator’s list, they’re given an online voucher so a “flu friend” can collect a course of Tamiflu.

“We’re not criticizing the current Department of Health policy, but we hope they’ll inform perhaps a slight shift in policy in terms of use of these drugs,” Thompson told CNN.

The British Department of Health said the report was right to suggest bed rest and over the counter remedies for people with mild cases of flu, but added that it was potentially dangerous to deter people with severe cases of flu from taking Tamiflu, including children.

In a statement, a spokesman said: “Whilst there is doubt about how swine flu affects children, we believe a safety-first approach of offering anti-virals to everyone remains a sensible and responsible way forward. However, we will keep this policy under review as we learn more about the virus and its effects.”

The British Medical Association (BMA) also adopted a cautious stance. The chairman of the BMA’s general practitioner’s committee, Dr Laurence Buckman, said doctors always have to balance the risk of major complications from swine flu with the potential side-effects of anti-virals.

“While we know they are safe, we do know that vomiting and diarrhea can occur in some children and adults who take them,” he said, adding “The more we learn about these drugs the more we will know how to treat patients with the most up-to-date clinical evidence.”

Blog posts from study authors posted on BMJ website:

Carl Heneghan

The last few days has been hectic since the publication of our systematic review in the BMJ on the use of antivirals in children.  By now, you are probably aware of the findings given the media interest. Basically, our study raised questions about the usefulness of antiviral flu drugs in preventing and treating flu in children, indicating the harmful effects may not be justified by the limited benefits provided. This puts us in direct conflict with the DOH policy of antivirals for all. I think what is important in the present pandemic is to remember how we spent a number of years preventing a similar strategy with the use of antibiotics in sore throat; especially when the published research showed limited benefits in mild disease and the emergence of resistance became a real issue.  We have been slightly overwhelmed by all the media but are trying to keep a cool head. Having just come out of an interview on the Becky Anderson Show on CNN live at 9 O’clock on Wednesday there are a couple of things I have learnt over the last few days that have been helpful.

One is to keep up-to date with the news on a daily basis. Why? Well when you are live on TV and the interviewer asks you in a forceful way:

“WHO continues to recommend use of antivirals as treatment for people who are severely ill or are at risk of other health complications,”  “isn’t your advice in direct conflict with the WHO? “

Difficult question to answer when you are on live TV and you are about to directly question whether the WHO advice is correct. However, as I said keeping up to date is the trick, because if you read the rest of the guidance it goes on to say:

“However, it also stressed that the antiviral, made by Swiss pharmaceutical giant Roche, should not be taken by those showing just mild flu-like symptoms”

Having knowledge of and being able to reverberate the above statement made the whole interview go much smoother. Over the last few days Matthew and I have also been canvassing a number of GP colleagues to see where they stand on this and reassuringly they are in accordance with the advice in mild disease.

On a lighter note, what is the best way to keep up to date? I find google news and reader effective. You can easily set yourself up email feeds for key words and guidance and alerts on google reader. Also, believe it or not, I find twitter very useful: I follow about 50 people or organizations – such as the BMJ who give great information and updates on news stories as they emerge: but, because they only have 140 characters you never feel overwhelmed by the amount of information provided. Finally doing the press briefings with two of you makes it a lot easier; you can bounce ideas off each other, check where you are up to and distribute some of the workload around so you can meet all of the commitments. 

Carl Heneghan is Clinical Lecturer and Deputy Director of the Centre for Evidence-Based Medicine in the Department of Primary Health Care at the University of Oxford. He is also a General Practitioner.

Matthew Thompson

The last few days have been a bit of a whirlwind, with normal work and meetings put on hold for now. Fortunately, I have a quiet day in surgery this week, so managed to gather thoughts and do some real work and see some real patients.

This is certainly the biggest press event I have been involved in, and suspect the same is true for our Department. Left me thinking how often the BMJ gets such international attention.  Overall, it was great to have a paper fast tracked in the BMJ -  the usual weeks or months of waiting to hear about reviews etc was compounded into a couple of weeks, and at times days. What this meant was rapid fire back and forth responding to the journal, editor and proof reader comments – helpfully all fielded by Carl while I managed to drag myself away from my holiday in France to check manuscript versions etc at a cyber cafe.

I thought the paper would generate some press interest, but was honestly surprised that it has been such a big story. I suppose the combination of swine flu, children, government policies, big pharma etc. was too much to ignore, especially on a relatively quiet week in the press.

The question now in my mind, is what to make of the media onslaught that followed? First of all I was amazed by the skills of many of the reporters - they seemed to be able to turn new information (after all we have been working on this paper for a couple of months, they had a few minutes) into coherent questions and statements for live TV. They did this incredibly rapidly. For instance it took the BBC four minutes to post the story online after the embargo time.  Carl and I both did a bunch of live interviews on TV and radio. Years ago, I used to be terrified to put my hand up in the class at school (you know the shaky voice, trembling chest type anxieties); but overtime the nerves for these big occasions have lessened. I think the major issue is being confident in knowing what you are talking about form a knowledge and a methodological aspect

In terms of live TV interviews what I found tricky was looking directly into the camera (which you cannot really see as it is disguised in some black hole), while being blinded by studio lights, while the producer is giving you a countdown in one ear, and all the time trying NOT to look at the screen, with the live pictures on it, which were always curiously situated off to one side. If you do look at the screen to the side then you have the appearance of looking really shifty!

Was the reporting fair? Well mostly it was. Clearly no-one is going to report the umpteen thousand words of carefully crafted systematic review, so very brief take home points were inevitable. A few of the headlines were ever so slightly over the top, i.e. the “pig flu drug bad for children”, and you could clearly see how both the print and TV would try to grab attention with a catchy headline followed by more balanced report.

As the media interest died down (as it inevitably does), I wondered if it had been too over the top.  A day in surgery was a good way to reflect on it all, none of my patients mentioned that they had seen me on the news, which I was kind of glad about. It was nice “just” being a GP for a day again and focussing on day to day clinical problems (interesting no-one with suspected swine flu that day though…).

Should we have done a press release at all, or just let it sneak out there via the on line BMJ and eventually trickle into the news? Well, we believed the research and our conclusions were valid, and that we were addressing a really important clinical problem …..so why not? Should we have told the UK Department of Health first, or asked for comments from the WHO, or the pharmaceutical manufacturers of the antivirals….. where would you stop? What if they didn’t really like our conclusions, would we have changed anything? Not really. So, if the point of research is to actually inform clinicians, patients, policy makers etc, I think we were right to get this particular research study out there into the world.

Matthew Thompson is a GP in Oxford, and a clinical scientist at the Department of Primary Health Care at the University of Oxford. He trained originally in Glasgow, but has since worked in South Africa and the USA as a GP. He combines GP work, with research mostly into children’s health issues in primary care, as well as teaching evidence based medicine and supervising academic GP fellows

Study Information:

Matthew Shun-Shin, Matthew Thompson, Carl Heneghan, Rafael Perera, Anthony Harnden, Anthony Harnden, David Mant. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. British Medical Journal 2009 August 
Kadoorie Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, Oxford University Department of Primary Health Care, Rosemary Rue Building, Headington, Oxford OX3 7LF.

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