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"Black Box" Warning Regarding Long-Acting Bronchodilators

In 1996, The Salmeterol (Serevent) Multicenter Asthma Research Trial (SMART) was begun to compare the safety of the long-acting bronchodilator Salmeterol when it was added to asthma therapy.

There have been several difficulties associated with this study. One problem was finding enough eligible subjects. The initial goal was to enroll 60,000 patients, but because no patient could enroll in this study if he or she had previously used any long-acting bronchodilator (LABA), the final study population consisted of only 26,355 participants.

Another problem encountered by this study was that asthma severity among the patients was not the same. The African-Americans' asthma was more severe than the Caucasian subjects. In addition, medication compliance with using inhaled corticosteroids (ICS) was substantially lower among the African-American subjects (38% compliance) versus 49% for the Caucasian patients. This is extremely important because inhaled steroids (ICS) are the medicine of choice for all forms of persistent asthma - mild, moderate or severe (Suissas et al. "Low-dose inhaled corticosteroids in the prevention of death from asthma" New England Journal of Medicine 2000),

In October 2005, the US Food and Drug Administration (FDA) imposed a "black box" warning on both salmeterol (Serevent) and the salmeterol-fluticasone (Advair) combination (even though the inhaled steroid, fluticasone, in Advair should prevent asthma morbidity and mortality).

The wording of this warning is as follows: "Data from a large placebo-controlled U.S. study that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179)".

In the "Warnings" section of the package insert is the following: "Data from a large placebo-controlled safety study that was stopped early suggests that salmeterol may be associated with rare serious asthma episodes or asthma-related deaths. Data from this study further suggests that the risk might be greater in African-American patients. The data from the Salmeterol Multicenter Asthma Research Trial (SMART) study are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk."

Based upon the above information, it is clear that LABA medication is not indicated in mild, intermittent bronchial asthma or mild, persistent bronchial asthma. The controversy arises for patients with moderate persistent, moderate-severe persistent or severe persistent bronchial asthma.

Since this black box warning was issued, there has been much discussion regarding appropriate treatment for patients with moderate, moderate-severe and severe-persistent bronchial asthma. In the January 2006 issue of the Journal of Allergy and Clinical Immunology, Harold Nelson, M.D., from National Jewish Hospital in Denver, Colorado, summarized the asthma literature and made the following statements and recommendations:

Short-acting Bronchodilators

  1. Short-acting bronchodilators, such as albuterol, are effective in relieving acute symptoms of asthma and, in the short term prevention of asthma symptoms.
  2. On the other hand, short-acting bronchodilators like albuterol are ineffective when used on a regular schedule to improve asthma control.
  3. With frequent administration, short-acting bronchodilators (when used alone), can become less effective over time.
  4. Frequent use (more than 2 or 3 times per week on a regular basis) of short-acting bronchodilators without concomitant use of ICS, has been associated with the increased risk of death and near-death from asthma.

Long-acting Bronchodilators (LABAs)

  1. LABAs provide sustained bronchodilitation and improve asthma control.
  2. LABAs by themselves have no significant anti-inflammatory effects, since airway inflammation is the cause of all asthma. LABAs should only be used with inhaled corticosteroids.
  3. LABAs added to inhaled corticosteroids enhance asthma control and decrease the occurrence of asthma exacerbations more effectively than does a doubling of the dose of ICS, and that is why the LABA/ICS combination is the preferred treatment for moderate and severe asthma.

LABA Effects on Asthma Control and Mortality

  1. Prospective studies of both salmeterol and formoterol (Foradil) (another LABA), when used alone, have identified an increased risk of death or near death fatal outcome.
  2. Studies have not identified an increased risk of deaths or near death fatal outcomes in patients using both LABAs and ICS at the same time.

In conclusion, LABAs should only be administered to patients with moderate or severe persistent asthma, and should always be used in combination with inhaled corticosteroids.