Is Advair Dangerous?

By Dr. Paul Ehrlich

The combination asthma treatment Advair seems to come up every few years in terms that paint it as a grave threat to public health. Larry has written about it a couple of times on this website and we wrote about it in our book. Advair and Symbicort are a class of inhalers that combine an inhaled corticosteroid (ICS) to ease asthma inflammation with a long-acting beta agonist (LABA), which helps relieve bronchoconstriction, tightening of the small airways in the lungs. Advair, which uses the steroid fluticasone and the bronchodilator salmeterol, was the first and is by far the biggest in the category. The consensus is that the two drugs taken together are safe, whereas the beta agonist taken without a steroid is dangerous. Easing bronchoconstriction without alleviating the inflammation can indeed be hazardous, and it has long been allergists’ practice not to prescribe a LABA like Severent without an accompanying steroid like Flovent, or to combine the two in Advair or another dual treatment.

The current version of the saga comes in a massive report on Pro Publica, Journalism in the Public Interest, called “Overuse, Safety Cloud Advair’s Ascent to Asthma Blockbuster” by two-time Pulitzer Prize winner Jeff Gerth.

Once again, the devil in the details is salmeterol, but the Great Satan by the reporter’s reckoning is GlaxoSmithKline, which has sold $80-billlion in sales worldwide in part by marketing Advair, the most expensive drug in this category, aggressively to too many patients through a network of reps hyped up by pep rallies and incentives. As more treatments entered the category, Glaxo took aim at milder cases for which Advair was not originally deemed appropriate. Whistle-blower lawsuits, discovery from suits filed by patients’ families, and intervention by regulators and the Justice Department have revealed this expansionist marketing strategy.

I was there at the beginning. I don’t remember Advair being marketed any more aggressively than any other new product, even in those days when drug companies were allowed to be much more generous with doctors than they are now. I saw it as a convenient solution to a very big problem—namely that many asthmatics were not responding to steroids alone, they needed treatment for bronchoconstriction, too, but every time an additional drug was added to the daily regimen, it came at the expense of adherence. This isn’t new in the annals of human behavior. It has been around at least since the supermarket started replacing the neighborhood butcher and greengrocer.

It has also done a lot of good. In those days, too many asthmatics kept their asthma at bay by too-frequent puffs on their prescription albuterol (and still do) or their non-prescription Primatene (now banned), which may have allowed them to breathe but did nothing to control dangerous inflammation. The combination medicines have undoubtedly saved lives. As it is, the 3500 or so U.S. asthma deaths a year are substantially lower per capita than those in nations like the U.K. and Australia. Maybe the blanket prescription of Advair helps, although far too much asthma is uncontrolled.

On the other hand, there are bound to be patients being treated in this one-size-fits-all mode for whom salmeterol is dangerous. This plays right to one of the foundational tenets of our book and website, which is the idea that the study of asthma is the study of one patient. That asthma is a syndrome, a collection of symptoms, not a single disease. A family practitioner looks at a wheezing patient and sees asthma. A pulmonologist may see asthma or COPD, but she may not see allergies. An allergist might see allergies, but not non-allergic asthma. The more we learn about the different conditions that cause asthma symptoms, the more possibilities that we will uncover cases where popular broad-spectrum drugs may not work, or make things worse.

For example, the kind of asthma that is most successfully treated with inhaled steroids is characterized by the white blood cells called eosinophils, which are drawn to inflammation. When there is accompanying bronchoconstriction, in which small airway muscles are flexed, trapping mucus, allergens, microbes, viruses, and air pollutants, a jolt of a short-acting beta agonist can open them up and a LABA can help keep them open while the steroid keeps inflammation at bay and the eosinophils go away. Then we can “step down” to steroids alone.

However, some asthma is neutrophil dominant, and doesn’t respond to steroids. A patient who takes Advair for this is really just taking salmeterol, with all the attendant dangers. Relieving bronchoconstriction alone may provide some relief, but the underlying condition may continue to simmer. As a practicing allergist, I don’t have the resources to routinely distinguish between eosinophilic asthma and neutrophilic, such as sputum cultures, which are a particular drag for children. But if I give a new patient Advair to get inflammation under control, and hope that I can reduce the prescription to ICS only, I ask to see him again in six or eight weeks to see what’s going on. Allergists joke darkly that pulmonologists will prescribe and make an appointment for six months, then wonder if they will ever see the patient again.

I can’t speak to the marketing of Advair. I have no reason to doubt the accuracy of Gerth’s reporting from a business point of view, but I believe it is not particularly nuanced from a medical point of view. MDs should not make decisions the way MBAs do, and it is the MBAs who are making the marketing decisions.

This situation is about to be further complicated by the addition to some combination inhalers of another drug called ipratropium bromide (Atrovent, et al) which is used for bronchospasm and COPD. I’m uncomfortable about this. For one thing, I worked with this drug when it was being developed 40 years ago during my fellowship at Walter Reed. Combining it with two other old drugs and calling it something new is not the kind of innovative thinking I would like to see applied to asthma treatment. This may not be rearranging deck chairs on the Titanic. More like lifeboats. Some patients may benefit, but as with Advair, there may be a few fatalities as well. Two-out-of-three medication strategy may be a good business decision, but “treat ‘em all and let God sort ‘em out” is not what I was trained to do.

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