Neuraminidase inhibitors for influenzaBMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2548 (Published 09 April 2014) Cite this as: BMJ 2014;348:g2548
- Harlan M Krumholz, Harold H Hines Jr professor of medicine
- 1Department of Internal Medicine, Yale University School of Medicine New Haven, CT 06510, USA; Department of Health Policy and Management, Yale School of Public Health; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital
Informed choice requires comprehensive and credible information. Much of the rationale for the currently evolving movement to fully share data is to provide information for decision making, particularly in situations involving the need to balance the potential benefits and harms of medical products. This investment in data sharing is based on the premise that the value of the information from unavailable data is sufficiently meaningful to be worth the effort to make them available.1 Presumably, patients, with guidance from their doctors, might choose differently if data owners were to release all the information relevant to specific treatments and if independent scientists were able to properly analyze and communicate the results.
The publication of the most recent iteration of Cochrane reviews on the benefits and harms of oseltamivir and zanamivir, two neuraminidase inhibitors approved for the treatment of influenza, marks the first time that reviews of these products included information from all the pertinent clinical trials conducted by the manufacturers.2 3 Prior reviews could consider only a proportion of the studies that scientists had conducted with the drugs, since many were unpublished or selectively published. As a result of having much data out of public view, the prior reviews expressed substantial uncertainty about the benefits and harms of these antiviral agents, which led to repeated requests for all data to be made available.4 5
Even in the absence of full transparency regarding the risks and benefits of oseltamivir and zanamivir, the medical establishment embraced the drugs. Sales garnered billions of dollars. Moreover, governments stockpiled the drugs, presuming that their potential public health benefit merited the substantial investment. During this period, authoritative sources, based on a medical literature with less than all of the trial results, suggested that oseltamivir and zanamivir provided benefit with minimal risks. For example, the United States Centers for Disease Control and Prevention states: “For people with a high risk medical condition, treatment with an antiviral drug can mean the differences between having a milder illness instead of a very serious illness that could result in a hospital stay.” The agency further states that the drugs work best if started within two days of illness, but “starting them later can still be helpful, especially if the sick person has a high risk health condition or is very sick from the flu.” The National Institute for Health and Care Excellence (NICE) of the United Kingdom states that oseltamivir and zanamivir are indicated for patients who have a high risk of complications.6 7 The recommendations from the American Academy of Pediatrics state: “Investigators have consistently found that timely oseltamivir treatment can reduce the risk of complications, including those resulting in hospitalization and death.”8 The World Health Organization lists oseltamivir as an essential medicine for adults and children.9 Interestingly, the US Food and Drug Administration, which did have access to all the trial data, required the label for oseltamivir to indicate that it has not been shown to prevent bacterial infections.10
With the comprehensive new reviews based on all the data, the perspective has changed substantially.2 3 The previous findings that symptoms can be shortened by about half a day (from about a week in the placebo group) remain, but, with all the evidence available from treatment and prophylaxis studies, it has become clearer that convincing clinical trial evidence of a reduction in the risk of hospitalization or complications is lacking. Moreover, the reviewers found that oseltamivir causes nausea and vomiting and increases the risk of headaches, renal problems, and psychiatric syndromes. Zanamivir had fewer adverse effects but also had no demonstrated effect on complications or hospitalizations. The drug did reduce symptoms by about half a day, but the reviewers found that it may be no better than other symptom relief medications. For prophylaxis, zanamivir significantly reduced the risk of symptomatic influenza, but there was heterogeneity among the studies and sample sizes were small. In addition, there was no difference in asymptomatic influenza. There were similar findings for oseltamivir, and the investigators noted that there was partial reporting of influenza-like illness. The findings are hardly definitive.
Unless other evidence or analyses demonstrate more conclusive proof of benefit over harm, it is difficult to conceive that many patients would actively seek treatment. The benefits involve a shortening of symptoms that few patients would find worth the risks of incurring the harms of treatment. From a health system perspective, the enormous expenditures do not appear to have commensurate benefit.
Unfortunately, even with all the existing data in view, many questions linger, which is remarkable given that the drugs have been approved for 15 years. A large, definitive set of clinical trials performed by an independent group and focused on patient groups that are currently understudied, including children, has yet to be conducted. Until it is, we know too little about the heterogeneity of effects and whether there are people who are more likely to benefit and less likely to be harmed. In most of the studies, the number of events is too small to assess heterogeneity—and even with pooling all the subjects, the confidence intervals are wide. There is some question over whether complications were systematically collected or reported in many trials. Moreover, the burden of the complications is not well characterized, making it difficult to determine how patients experience them. The usefulness for prophylaxis is uncertain given the size of the studies. Finally, the incremental benefit of these drugs compared with other symptom relief medications is based on only a small number of studies. Given the number of people each year affected by influenza, it would seem very possible to obtain answers to these questions in one winter.
For now, health professionals can communicate the available evidence to anyone contemplating taking oseltamivir and zanamivir for prophylaxis or treatment, with confidence that nothing is hidden from view. Many patients may consider the risk of adverse effects to more than offset the prospect of shortening symptoms by half a day. For those who pay out of pocket, the additional costs may also be a deterrent. Of primary importance for decision makers is that now, with all of the data available for others to evaluate, the knowns and unknowns can be laid out clearly, revealing the weakness of the evidentiary support for these products and what exactly we need to learn for the future.
Cite this as: BMJ 2014;348:g2548
Funding: I am supported by grant U01 HL105270-04 (Center for Cardiovascular Outcomes Research at Yale University) from the National Heart, Lung, and Blood Institute in Bethesda, Maryland, USA.
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: I have received research grants from Medtronic and from Johnson & Johnson, through Yale University, to develop methods of clinical trial data sharing; I am chair of a cardiac scientific advisory board for UnitedHealth.