The Controversy That Won’t Go Away

John Fauber, an investigative reporter, for the Milwaukee Journal Sentinel and the on-line publication MedPage Today, wrote an article published November 18 called “Advair: How Safe Is This Drug?”

In it he notes that Advair (and other similar medications, such as Symbicort and Dulera) contain two types of medications, an inhaled corticosteroid to suppress asthmatic inflammation and a long-acting beta-agonist bronchodilator to reverse or prevent constriction of bronchial muscles. He then references concerns about the safety of the long-acting beta-agonist bronchodilators, which “have been linked to 1,900 asthma deaths from 2004 through 2011, according to an estimate provided by AdverseEvents Inc.” He goes on to cite a separate analysis in 2008 by a researcher with the Food and Drug Administration, Dr. David Graham, that “estimated the drugs contributed to 14,000 asthma deaths from 1994 through 2007.”

Many physicians, like us, witnessed the dramatic improvement in the quality of life of persons with difficult asthma when the long-acting beta-agonist bronchodilators (salmeterol and later, formoterol) were first introduced in the 1990s. In Advair, two medications (salmeterol and fluticasone) delivered simultaneously from one device brought good asthma control to many who had struggled for years with frequent symptoms, asthmatic attacks, and complex inhaler regimens, sometimes including recommendations such as “take 4 puffs 4 times a day” of your triamcinolone inhaler (Azmacort). Remember that?

So how is it possible that these same highly effective medications are associated with an increased risk of death? Not cardiac deaths, but deaths from asthma attacks.

Here’s what we know:

•   Treatment with long-acting beta-agonist bronchodilators alone, without treating at the same time with an inhaled steroid such as fluticasone (Flovent), budesonide (Pulmicort), beclomethasone (Qvar), and others, is associated with more asthma attacks than treatment with an inhaled steroid alone.

•   Increased sales of the short-acting beta-agonist bronchodilator, isoproterenol, were associated with increased deaths among asthmatics in England in the 1960s; and increased sales of a different short-acting beta-agonist bronchodilator, fenoterol, were associated with increased deaths among asthmatics in Australia in the late 1970s. In neither instance were inhaled steroids combined with these beta-agonist bronchodilators.

•   In a large multi-center research study, when the long-acting beta-agonist bronchodilator, salmeterol, was compared to placebo among persons with asthma taking their “usual therapy,” whatever it might be, more people randomly assigned to receive salmeterol died from asthma attacks than those given placebo. Most of the persons in this study were not taking inhaled steroids.

Here's what we don't know:

•   Why are long-acting beta-agonist bronchodilators potentially harmful when used without concomitant anti-inflammatory therapy? Is it because persons with asthma come to rely on medications that relax bronchial smooth muscle and ignore the allergic swelling of the bronchial tubes and excess mucus production that can lead to fatal obstruction of the breathing passages, or is there some other mechanism?

•   If you use an inhaled steroid together with a long-acting beta-agonist bronchodilator, is the increased risk of a life-threatening attack eliminated? This question is currently being addressed by a series of long-term research studies comparing inhaled steroids alone versus inhaled steroids combined with long-acting beta-agonist bronchodilators. We will need to wait until 2017 to get the results of these investigations.

What do we conclude in the meantime?

We are struck by the fact that despite booming sales of Advair and similar medications over the past decade, asthma deaths in the United States have steadily declined. And we are reminded that the concern regarding the safety of long-acting beta-agonist bronchodilators relates to severe, fatal asthmatic attacks, not heart attacks, irregular heart rhythms, or mysterious sudden death. We believe that medications like Advair, combined with routine medical care, help to achieve good asthma control and protect against asthmatic attacks. If you are taking an inhaled steroid together with a long-acting beta-agonist bronchodilator, you and your doctor working together can ensure that you are safe from life-threatening asthmatic attacks.

P.S. Neither Dr. Sloane nor Dr. Fanta receives financial incentives of any sort from the pharmaceutical makers of Advair and related drugs.