Long-acting Beta-agonist Bronchodilators

The long-acting inhaled beta-agonist bronchodilators, salmeterol (Serevent, Advair) and formoterol (Foradil) have been available to treat asthma since the 1990s. The Food and Drug Administration (FDA) has instructed that a “black-box warning” be added to the informational package inserts of these medications (starting in November, 2003); and in 2006 FDA Public Health Advisory was issued to caution medical providers about potential risks associated with their use. This brochure has been created to explore the source and meaning of these warnings.

What are long-acting beta agonists?

The beta agonists make up a class of asthma medication that works by stimulating the muscles surrounding the bronchial tubes to relax, thereby opening the airways wider. Almost every patient with asthma will carry a quick-acting beta-agonist bronchodilator to be used as a “rescue medication” for rapid relief of symptoms. Examples include albuterol (Proventil, Ventolin, Xopenex), pirbuterol (Maxair), and metaproterenol (Alupent). The effect of a dose of these medicines wears off after 3-4 hours; they are quick-acting, but their benefit is of short duration.

By contrast, the long-acting beta agonists continue to work to open the airways for 12 hours or more. They are meant to be used as a “controller medication” for asthma, taken every day, twice a day, for prevention of asthmatic symptoms. They are sold alone as the Serevent Diskus and Foradil Aerolizer. In addition, the widely-used Advair Diskus contains the long-acting beta agonist, salmeterol (Serevent), mixed in combination with an inhaled steroid, fluticasone (Flovent). It is recommended that the long-acting beta agonists be used in combination with an anti-inflammatory medication, such as the inhaled steroids. Examples of inhaled steroids are Aerobid, Asmanex, Azmacort, Budesonide, Flovent, and Qvar.

Since they were first introduced, the long-acting beta agonists have been shown to be very effective in improving asthma control. For many people with asthma, the benefit has been dramatic: fewer asthma symptoms at rest or with exercise, fewer night-time awakenings due to asthma, less need for rescue medications, fewer days missed from work or school due to asthma, and fewer asthma flare-ups or exacerbations. National and international guidelines published to advise doctors regarding optimal treatment of asthma all recommend the use of long-acting beta agonists for asthma that is considered more severe than just mild asthma.

The source of concern regarding long-acting beta agonists

However, you should be aware that recent studies regarding the use of long-acting beta agonists have suggested that in rare cases severe asthma attacks and deaths may be associated with their use. In the largest of these studies, more than 26,000 people with asthma were recruited to test the safety of salmeterol (Serevent). Half of the people with asthma were given salmeterol to use twice daily; the other half received a placebo inhaler to use twice daily. All patients were monitored by follow-up telephone calls for ½ year with the goal of determining any differences in harmful events or outcomes.

Serious adverse outcomes were rare in both groups (<1%). However, this study found more severe asthma exacerbations and more asthma deaths in the group randomly assigned to take salmeterol rather than placebo. The reason for this observation is unknown. Further analysis of the results suggested that you were at risk for these severe asthma outcomes if you were: 1) African-American (a group that had more severe asthma on entry into the study); 2) not using an inhaled steroid for asthma control; and 3) recruited into the study by radio and television advertising (and therefore less likely to be getting regular medical care) than if you were recruited by a physician-investigator in whose practice you were receiving your medical care. The study could not answer the question as to whether combining use of an inhaled steroid with a long-acting beta agonist eliminated the risk of life-threatening asthma exacerbations observed with the long-acting beta agonist.

Potential explanations for these findings

Quite frankly, we do not know why the use of salmeterol (Serevent) is associated with a greater risk (though rare) of severe asthma exacerbations and asthma deaths. One potential explanation is the following. Patients who use a long-acting and powerful bronchodilator alone without an inhaled steroid feel better, but they fail to treat the inflammation of their bronchial tubes. With exposure to allergens and irritants, their airways swell and fill with mucus. Their asthma worsens despite using an effective bronchodilator medication, and they may fail to seek appropriate medical attention for their poorly-controlled asthma. Worse still, they may turn to their long-acting bronchodilator for quick relief (as a “rescue medication”), for which it is not intended.

Experiments conducted in patients with moderate and severe asthma support this potential explanation. When salmeterol (Serevent) was added to the treatment with an inhaled steroid that they were receiving, their asthma came under better control. If the inhaled steroid was then stopped – and they continued to take the long-acting beta agonist alone – their risk of an asthmatic attack rose several-fold compared with the group that continued the combination of an inhaled steroid and a long-acting beta agonist. It is clear that for people with more than mild asthma, treatment with bronchodilators alone (to relax the muscles of the bronchial tubes) without anti-inflammatory steroids (to reduce the swelling of the walls of the tubes) is not a good strategy.

Though plausible, this explanation may not be the whole story. Other reasons are also possible for the association between long-acting beta agonists and bad outcomes in asthma. One observation that is currently being explored (by researchers at Partners Asthma Center and elsewhere) relates to differences in the population as to how we react to beta-agonist bronchodilators based on variations in our genes. A small percentage of the population may inherit a genetic predisposition that causes a slight worsening of lung function when beta agonists are taken regularly. And it remains possible that the long-acting beta agonists have other pharmacologic effects in asthma that we have yet to recognize.

Using long-acting beta-agonist bronchodilators safely

For many of our patients with moderate or severe asthma, we continue to prescribe the long-acting beta agonists. In many instances they provide dramatic, sometimes life-altering benefit. But we also take seriously the new warnings about the risks associated with their use. When we recommend their use, we do so as part of a comprehensive program of asthma management. This program includes avoiding as much as possible the triggers that cause your asthma and allergies to flare; periodic review of your medications to ensure the optimal treatment regimen; monitoring for deteriorations in your asthma; and developing a plan to deal with flare-ups before they become dangerously severe (your “asthma action plan”). You can help by taking your medications as prescribed, being alert to signs that your asthma is worsening, communicating with your asthma providers when you are not doing well, and keeping your regular follow-up medical appointments. We share with you the same goal: an active and safe life unrestricted by asthma or its treatments. Together we can achieve this goal, using the best available treatment program.

Points to remember about the long-acting beta agonists:

• Do not use your long-acting beta-agonist inhaler as a rescue medication for quick relief of symptoms.
• In most instances, long-acting beta agonists should only be used in conjunction with an inhaled steroid.
• If your asthma seems to worsen after starting a long-acting beta-agonist bronchodilator, notify your asthma care provider.
• If you are taking a long-acting beta agonist and suffer an asthmatic exacerbation that does not respond normally to quick-relief treatments, seek medical care promptly and notify your asthma care provider.