番茄社区

Oseltamivir (Tamiflu) has not panned out for reducing the risk of influenza hospitalization, according to a large meta-analysis.

Among over 6,000 flu patients across 15 studies, the 0.14-percentage point difference in hospitalization rate between those who took oseltamivir and those who did not was not significant (RR 0.77, 95% CI 0.47-1.27), Emily McDonald, MD, MSc, of McGill University Health Centre in Montreal, and colleagues reported in .

"I wouldn't prescribe it to an otherwise healthy person," McDonald told 番茄社区. "There was little evidence that it would prevent you from going to the hospital."

What's more, she added, "it's not completely benign. It does cause uncomfortable side effects."

Patients taking the antiviral were more likely to have gastrointestinal (GI) side effects, including nausea (RR 1.43, 95% CI 1.13-1.82) and vomiting (RR 1.83, 95% CI 1.28-2.63), according to the study.

"That side effect might lead to dehydration, and so it could be more pronounced in older people or people who have a tendency towards dehydration -- people with diabetes might be more affected by it," McDonald said. "So certainly, for some populations, it could be more harmful than just a nuisance side effect."

Oseltamivir is indicated for prophylaxis and to treat acute, uncomplicated influenza in patients symptomatic for no more than 2 days. In fact, the U.S. government has a stockpile of the antiviral medication as part of its national pandemic responses.

Studies have shown the antiviral helps speed recovery from influenza. And a recent pediatric study showed evidence that the medication reduced length of stay, readmission, intensive care transfers, and death for children with influenza who were given the antiviral treatment, notably for those that were treated the day of admission.

"There is good evidence that oseltamivir, a drug of known antiviral activity, shortens the duration of influenza when administered within 48 hours," Arnold Monto, MD, from the School of Public Health at the University of Michigan in Ann Arbor, told 番茄社区 by email.

However, McDonald's group characterized this 16.8- to 25.2-hour reduction as "small."

"Whether this decrease is meaningful when compared with medication costs, an increase in nonsevere adverse events, and the opportunity cost of missing out on the discovery of more effective therapies is a topic of study for health care economists and could be discussed on an individual patient basis," they wrote.

McDonald contended that the current oseltamivir treatment recommendations may need to be reviewed. "I hope that we stop using it in populations where we don't see an important effect, and I hope it inspires researchers to run the study that is needed, which is a large placebo-controlled randomized trial in the highest-risk individuals."

Influenza resolves on its own, she explained, but sometimes there's no time to explain that to a sick patient. "The barrier to prescribing is lower than the barrier to explaining why you don't need to take a medication or why you shouldn't prescribe something; sometimes time pressures in the office can lead to us prescribing treatments that are not as effective as we'd like them to be."

A prescription for rest and hydration may be what the majority of patients need most, she added. "Overprescribing is a big problem ... We do tend to prescribe antibiotics and antivirals more than we need to."

The meta-analysis didn't suggest a benefit in high-risk populations overall (RR 0.90 vs 0.63 in lower risk patients). Still, patients in selected higher-risk groups could benefit from oseltamivir, and that should be discussed, she said.

"I might prescribe it to someone with a kidney transplant, someone at high risk for getting very sick and with a lack of immune system to fight the infection," McDonald noted.

McDonald and her colleagues noted that in further subgroup analysis, older adults with mean age of 65 or older (RR 0.99, 95% CI 0.19-5.13) appeared to gain even less than those younger than 65 (RR 0.72, 95% CI 0.39-1.34).

Monto noted that duration of illness was what previous studies had been aimed at showing, whereas the hospitalization endpoint used in the meta-analysis had a low event rate -- occurring in only 0.6% of non-treated individuals. "As the authors themselves state, it would have taken a far larger study to show a significant effect."

"Accordingly, the current recommendations for treatment should stay in place," he told 番茄社区. "Interesting, the authors did not find any of the more severe side effects that some have attributed to the drug. Only the GI side effects that all accept as related."

Of 2,352 studies found in the literature, 15 were included in the meta-analysis; nine of these (60%) were sponsored by Roche and were conducted between 1998 and 2006.

Criteria for study inclusion included having data on hospital outcomes for patients age 12 and up with confirmed influenza (PCR test or viral culture) who received an oral dose of 75 mg of oseltamivir twice daily for 5 days and having a comparator group of placebo or standard of care.

Of the 6,295 individuals (mean age 45 years) in the intention-to-treat population among the 15 included studies, 54% were female, with 70% identifying as white and 21% as Asian. Most (60%) of the cases were confirmed to be influenza A.

The authors noted study limitations, including that both industry and non-industry trials were included, a young mean age of patients, data on only first hospitalizations, and exclusion of high-dose treatment with oseltamivir and of observational data.

The results included all-cause hospitalization with influenza, rather than hospitalization with influenza only, in order to include hospitalizations that may be due to side effects of oseltamivir. "This is particularly relevant for older high-risk adults where seemingly mild gastrointestinal adverse effects might still increase the risk of hospitalization through anorexia and dehydration," the researchers explained.

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