In October, Merck Pharmaceuticals decided to withdraw its pain reliever and anti-inflammatory medication, rofecoxib (Vioxx^®), from the market. Post-marketing studies (that is, studies conducted after the medication had been approved for sale by the Food and Drug Administration [FDA]) found that use of Vioxx^® for 18 months or more was associated with a significant increase in the risk of heart attacks and strokes.

In the wake of this decision, the FDA is now being asked to review the safety of other prescription medications that were originally approved for sale in the United States but for which additional safety information has since become available. One of the five medications publicly mentioned for review is salmeterol (Serevent^®). Salmeterol is widely used to treat asthma and chronic obstructive pulmonary disease (COPD). Salmeterol is available for inhalation by Diskus^® device, either alone or in combination with an inhaled steroid, fluticasone (Flovent^®). The salmeterol-fluticasone combination inhaler, called Advair^®, is the most widely prescribed controller medication for asthma in the United States.

Studying the safety of Serevent^®

Why are there safety concerns about Serevent? In 1996, two years after FDA approval of Serevent^®, its manufacturers, GlaxoSmithKline, embarked on a large-scale experiment to assess the safety of Serevent^®. They felt the need to demonstrate its safety because of concerns that had been raised about potential harmful effects from regular use of this entire group of medications, called beta-agonist bronchodilators. Thousands of patients with asthma were asked to participate in this study, in which one group was given Serevent to take twice-daily and the other group received a placebo inhaler. Both groups of patients were advised to take their other usual asthma medications as they had before. The study lasted just over 6 months, and the question asked was: were there any differences in harmful respiratory outcomes in the two groups; that is, did one group have more asthma deaths or near-deaths (respiratory failure requiring use of a ventilator) than the other group?

The study, called the SMART study as an acronym for Salmeterol Multi-center Asthma Research Trial) was stopped in 2002 after approximately 26,000 persons with asthma (of the intended 60,000) had been enrolled. The study was stopped because of difficulty enrolling patients and the findings in African-Americans. Analysis of the results to that point found more asthma deaths (13 vs. 3) and life-threatening asthma events (37 vs. 22) in the Serevent^®-treated group. When the scientists conducting the study examined subgroups of patients, they found the following concerning results:

• among African-Americans, 5 times as many deaths and near-deaths from asthma occurred in those given Serevent^® than in those given placebo; and
• among patients with asthma not using an inhaled steroid as a preventive (controller) medication, again more deaths and near-deaths from asthma occurred in those given Serevent^® than in those given placebo. Only 38% of the African-Americans who participated in the study used an inhaled steroid.
  
  

Before continuing with our interpretation of these results, we need to acknowledge that publication of this newsletter, Breath of Fresh Air, is made possible in part by a generous educational grant from the makers of Serevent^®, GlaxoSmithKline.

What accounts for these findings?

The explanation for the findings in the SMART study – why Serevent was associated with more bad asthma outcomes – is unknown. Some have speculated that taking an effective bronchodilator (to open the breathing passageways by relaxing the bronchial muscles) without taking an anti-inflammatory medication (to prevent swelling of the walls of the bronchial tubes and excess mucus production) can lead to life-threatening asthmatic attacks because one is deceived into feeling that one’s breathing is satisfactory while all the while the breathing passageways become more swollen and clogged. Other explanations are possible, however, and future research will be needed to answer this question of “why?”

As a result of the findings from the SMART study, a warning was added to the informational insert provided with each package of Serevent^® and Advair^® inhaler:

• WARNING: Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT^® Inhalation Aerosol) 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).
  
  

Additional advice in the package insert suggests that:

• Patients should not stop SEREVENT^® or ADVAIR^® therapy for asthma or SEREVENT^® for COPD without physician/provider guidance since symptoms may worsen after discontinuation.
  
  

The question that may now go before the FDA is: should anything more be done to ensure patient safety, including potentially removing Serevent^® and Advair^® from the market?

What would you recommend?

Imagine that you are a member of the advisory board reviewing this information. You know of the concerns about the safety of Serevent^®, and you know too of the benefits of its use in combination with anti-inflammatory medications – fewer symptoms, improved lung function, fewer asthmatic attacks, and avoidance of the need for higher doses of inhaled steroids. You know that literally millions of people feel that they have been greatly helped by these drugs. What would you advise?

We at Partners Asthma Center continue to prescribe Serevent^® and Advair^®. We feel that the benefits outweigh the potential risks. We do not recommend that Serevent be used unless a patient with asthma is also taking a regular anti-inflammatory medication. And we believe that the best protection against life-threatening asthmatic attacks is not removal of long-acting beta-agonist bronchodilators from the market but good medical follow-up, knowledge about asthma and warning signs of severe asthmatic attacks, and a plan of action in the event that you suffer a severe asthmatic attack. Remember that the bad outcomes in the SMART study were life-threatening asthmatic attacks. You can remain safe from such attacks with good medicines and good medical care.