The Cycle of Salmeterol

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Salmeterol emerged as a promising new therapy for Asthma in the late 1980s. This was a novel long acting beta agonist (LABA), a bronchodilator that could control asthma symptoms for at least 8 hours. Because of its long lasting effects, it was used for treatment of nocturnal asthma, and put to rest the last uses of Theophylline, an oral asthma agent with potential life threatening toxicities such as cardiac irregularities and seizures.

Clinical trials for Serevent (Glaxo’s salmeterol product) started up in 1990. They looked at the efficacy of Serevent in a 12 hour period by monitoring pulmonary function tests and symptom scores in the office setting. These 12-hour days were done on Saturdays, and they camped out with study participants, who were fed pizza and treated to great movie classics such as “Conan the Barbarian” (starring the Governator, Arnold Schwarzenegger). Even though this was a blinded placebo-controlled trial, the effects of the active drug Serevent became obvious during the trial period. Lung function and symptom improvements lasted even throughout the 12-hour study period. This was destined to be a truly revolutionary therapy for asthma. When Serevent was latched on to the inhaled steroid Fluticasone in the mid 1990s as the Glaxo product Advair, a blockbuster asthma product was born. Advair was packaged in a then new dry powder formulation. Patients no longer had to coordinate their inhalations, as with the metered dose formulations. They just sucked in the Advair twice a day, and voila, their asthma was easily controlled. Glaxo made 3 different strengths of the product, geared to mild, moderate and severe asthma sufferers, thus covering the entire asthma market spectrum. Asthma practice was made much simpler, the need for the rescue medicine Albuterol plummeted, and the asthmatic’s life was made much easier. A landmark study from Europe, known as the FACET study (using a similar LABA, Formoterol) showed that patients on the combination LABA/ inhaled steroid formulation did better on all clinical parameters than those using inhaled steroids alone. Life was easy.

Then came the SMART study. This study appeared to show that patients on Salmeterol had an increased risk of death compared to those not on this agent for treatment of asthma. This was a giant red flag for standard asthma therapy. The study did have its drawbacks, however. Patients with Asthma and COPD (emphysema and chronic bronchitis) were enrolled. And the study implied problems with use of Salmeterol. However in practice, patients with asthma were almost never on Salmeterol alone, but rather on the combination product Advair, which included the greatly beneficial inhaled steroid Fluticasone. Asthma practitioners like myself were alarmed, but breathed a sigh of relief that our patients on Advair were safe.

That is, until the Annals of Internal Medicine published an article last week on a meta-analysis of studies done with Salmeterol. The meta-analysis confirmed that asthma patients on Salmeterol had a slight, but definite, increased risk of asthma exacerbations and death when using the product. The meta-analysis also showed that this danger, while mitigated by the concomitant use of inhaled steroids, was still there when using combination products such as Advair. An accompanying editorial advised providers to severely limit the use of Salmeterol to patients not adequately controlled on inhaled steroids alone, and suggested that Salmeterol may be withdrawn from the market.

Well, we all know where this story will end (think of Phen-Fen and Vioxx). Salmeterol will be withdrawn, and along with it, Advair. I do feel that Advair is an important and very useful agent in asthma, and that it’s demise will lead to a decrease in the control of asthma symptoms and quality of life. And in 17 years of practice I have not encountered a single major problem with this medication. But the data cannot be ignored. While the dangers are very slight, I will only rarely prescribe Advair from here on in, and will continue patients on Advair only if they have severe, uncontrolled asthma. Sic transit Gloria Pharmacopeia.