“The publication of this paper in 2006 has been met with a significant amount of anger and resistance from experts in the field, who are now struggling to reassess the safety of these drugs and revise recommendations for their use.”

Our meta-analysis clarifies the magnitude of risk associated with long-acting beta-agonist inhalers in asthma, and raises the possibility that conflicts of interest from pharmaceutical company funding may have influenced the promotion of these drugs. This pooled analysis of randomized trials showed that the use of long-acting beta-agonists, such as Advair and Serevent that are amongst the most prescribed drugs in the world, actually increase the risk of asthma hospitalizations and deaths by two- to four-fold compared with placebo.

There already had been some information in the literature and press about the potential risks of the inhalers, and the United States Food and Drug Administration (FDA) had considered taking them off the market in 2005, but it was thought at the time that the evidence was inconclusive. The results found in our meta-analysis are likely to be of high interest to practicing and research clinicians, as well as to regulatory review boards and the public.

This is clearly a synthesis of the available knowledge. It is interesting to note that many of the trials had reported twice as many people hospitalized for asthma in the treatment group compared with placebo, but because the results were not statistically significant this trend was generally ignored by researchers and practicing physicians. Our meta-analysis pooled the results from 19 trials to show a statistically and clinically significant 2.5-fold increase in asthma hospitalizations and a 4-fold increase in asthma deaths associated with long-acting beta-agonist inhalers.

Asthma is a common disorder associated with inflammation and constriction of the airways in the lung. Long-acting beta-agonists are inhalers that reduce constriction in the airways and improve symptoms such as wheezing and cough. However, due to the development of tolerance to their effects they actually decrease responsiveness to the drug over time and increase inflammation in the lungs, resulting in heightened reactivity to triggers that cause asthma attacks. Therefore, they end up improving the symptoms of asthma while at the same time making asthma attacks more frequent and severe.

I am an academic general internist and my field of interest is evidence-based medicine, which means that I look for standards of care that are at odds with the evidence. I have read studies over several years indicating that beta-agonists actually worsen asthma control and may be responsible for many of the asthma deaths.

In 2004 my colleagues and I performed a meta-analysis that showed that beta-agonist use results in tolerance to the drug’s effects after just one week of treatment. We also evaluated the potential conflict of interest that researchers may have due to pharmaceutical company funding.

Our review found that researchers with industry sponsorship were much more likely to say that beta-agonists were beneficial than those researchers without industry funding, even while evidence was surfacing that these drugs may be unsafe. The publication of this paper in 2006 has been met with a significant amount of anger and resistance from experts in the field, who are now struggling to reassess the safety of these drugs and revise recommendations for their use.

I believe the social implication is that physicians should not just believe everything that they read, but instead try to critically question whether the benefits of a given treatment outweigh the risks. The political implication is that our present system of research and FDA regulation may not place enough emphasis on assessing long-term safety of medications before they are heavily marketed. The Institute of Medicine has recently made a proposal for changes in our present regulatory system that could work toward ensuring the safety of prescription drug use.