I saw a patient yesterday, with previously poorly controlled asthma, who has now been under excellent control for years on Advair. She made an appointment to see me to discuss a concern she had. Her boyfriend saw an article in Men's Health about 8 drugs doctors would never take, and Advair was number one of the list. Though this is not the first or last misinformed report on the safety of asthma medications, I am hopeful that a soon to be published in the Annals of Internal Medicine will hopefully calm the fears of patients (and even some physicians).
The study looked at the safety of salmeterol when combined with an inhaled corticosteroid (ICS). The full report is currently embargoed, but the study is an analysis of of 66 studies with over 20,000 patients with asthma which showed that when the long-acting beta-agonist (LABA) salmeterol was combined with ICS it not only decreased the risk for severe exacerbations, but also did not increase the risk for asthma-related hospitalizations, deaths or intubations compared with patients who only used ICS alone.
There are currently two combinations products of an ICS and LABA, Advair (the 3rd most common prescribed drug in the US, with almost $4 billion in sales) and Symbicort (new to the market in the US, but used throughtout the world for years). ICS are the preferred treatment of asthma according to World Health and US asthma guidelines for both adults and children. In addition, for those patients who can not be controlled on ICS or have moderate persistent asthma, the combination of ICS and LABA are the most effective agents.
The controversy (and subsequent media frenzy) all started with the release of the The Salmeterol Multicenter Asthma Research Trial or SMART study which was designed to show safety of salmeterol. The study was stopped early because certain subsets of patients, particularly African Americans, seemed to have increased risk, including death. Though there have been criticisms of the study, the FDA applied a boxed warning not only to salmeterol, but all LABAs and products containing LABAs. However, by the time the study was finished, it was clear to most experts that LABAs should not be used alone. In fact, for the patients in the SMART study who were taking both ICS and salmeterol, there was no increased of death or worse asthma.
This makes a great deal of sense because asthma is predominantly a disease of chronic inflammation. When you treat the symptoms alone with a LABA but don't treat the underlying inflammation with an ICS, it is not a surprise that some people will have increase risk of serious asthma attacks and even death. The problem is that from the FDA's perspective, in order to prove that taking ICS plus LABA (i.e Advair, Symbicort) was just as safe as LABA alone, you would need to do another large, randomized trial. The SMART study would have needed 60,000 patients if it had gone to completion, so a study comparing ICS plus LABA to ICS alone looking at asthma hospitalization and death would need well over 120,000 patients since the risk for these events is so low. It does not appear that the NIH or other government agency would sponsor such an expensive study, and the pharmaceutical industry would similarly not be willing to make such an investment just to prove a point (that most doctors realize anyway). Thus, combination products like Advair and Symbicort will continue to have a boxed warning.
However, the new study soon to be published in Annals adds a considerable amount of reassurance. Since a randomized trial is virtually impossible, a meta-analysis (combination of similar studies) is the next best step. A previous meta-analysis (which received a lot of media attention and is mentioned in the Men's Health article) showed an increased risk, but all of the death data was based on the SMART study, and like the SMART study some patients were taking ICS and some were not. This new meta-analysis looks specifically for the risk of adding a LABA to an ICS. The fact that patients did better on the combination therapy confirms consistent data that the ICS plus LABA is better then ICS alone or other combinations. In addition, the fact that there were no additional deaths, hospitalizations or intubations is good evidence that though LABA's may be dangerous when used alone or with other asthma drugs, the appear to be safe when used in combination with an ICS (i.e Advair, Symbicort).
I am hopeful that when the article is released in its entirety, that it will receive at least half as much press as all of the other reports. Somehow, I doubt this.