A word of warning to asthma sufferers

By Nancy Shute
Posted 6/7/06

Are long-acting beta-agonists a lifesaving drug for people with asthma, or do they harm more than help? That's a question that has bedeviled asthma patients and their doctors almost since the powerful inhaled drugs came into use more than 50 years ago. Since 2003, spurred by evidence that some people who used the drugs to reduce the frequency of asthma attacks actually had their attacks become severe, the Food and Drug Administration has issued increasingly stern warnings about the risks posed by salmeterol and formoterol, sold as Advair Diskus, Foradil Aerolizer, and Serevent Diskus.

But the agency has kept the drugs on the market. Now a study in the June 6 online Annals of Internal Medicine, which analyzed existing data from 19 clinical trials involving 33,826 patients, suggests... the drugs shouldn't be used at all. The study, led by Shelley Salpeter, a clinical professor of medicine at the Stanford University School of Medicine, found that patients using long-acting beta-agonists were twice as likely to have life-threatening asthma attacks as patients on a placebo and 2.5 times more likely to be hospitalized. Death from asthma was rare, with only 16 patients studied dying. But those using LABAs were 3.5 times more likely to die, with 13 deaths as opposed to three in the placebo group.

What really snapped wide the eyelids of asthma researchers, however, was Salpeter's estimate that one LABA, salmeterol, could be responsible for 4,000 of the 5,000 asthma deaths in the United States each year. That conclusion seems "a little strong," says Thomas Platts-Mills, head of the department of asthma and allergic disease at the University of Virginia. If salmeterol were responsible for 80 percent of asthma deaths, Platts-Mills says, the mortality rate from asthma should have risen in recent years, as the drugs have been aggressively marketed. Instead, death rates have fallen in the past three to five years. That's not to say there aren't serious concerns about the drugs' safety, he says.

"I don't think it changes where we were when the FDA put a black box on any drug with salmeterol in it," Platts-Mills says. "But the idea that there's a national problem seems very unlikely." Patients should stick with current treatment guidelines for using LABAs, in the opinion of Jeffrey Glassroth, vice dean for academic and clinical affairs at Tufts University in Boston, who wrote an editorial accompanying the Salpeter study. That is, use inhaled corticosteroid drugs first to control asthma; these drugs help reduce inflammation that contributes to asthma. If symptoms don't improve, increase the dosage of corticosteroids before turning to LABAs. For many people, particularly those with severe asthma, LABAs, which relax muscles around the lung's airways, are very effective, Glassroth says. But for some, LABAs can make symptoms worse. "We don't have a way of predicting who's in that group," he says.

In the past, doctors worried that patients might be trying to use LABAs as rescue inhalers, which they are not. In its November 2005 health alert, the FDA urged patients to use only short-acting bronchodilators such as albuterol to treat wheezing during attacks, and to let their doctors know if wheezing got worse while using a LABA. Another theory is that LABAs mask asthma symptoms, and that patients taking them without corticosteroids may not realize their asthma is worsening in time to seek treatment. Many patients worry about using big doses of corticosteroids indefinitely, because the drugs can have serious side effects, particularly in children.

Other recent research suggests that people with a specific genetic variation may be less able to tolerate LABA drugs, but a test doesn't yet exist that makes it easy to screen people for that susceptibility.