A word of warning to asthma sufferers
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 bronchodilator drugs to reduce symptoms actually had their attacks become more 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. Unlike inhaled corticosteroid drugs, which are the first line of defense and which control asthma by reducing inflammation in the airways, these drugs work by relaxing airway muscles.
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. "I stopped using these drugs in my practice in the early 1990s," says Salpeter, who has an internal medicine practice in San Jose, Calif. Her observation that her patients' asthma was getting worse while using LABAs also prompted to her to do a meta-analysis, which interprets data from previously published research.
What really snapped wide the eyelids of asthma researchers was Salpeter's estimate that one widely used LABA, salmeterol, was 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 dramatically in recent years, as the drugs have been aggressively marketed. Instead, asthma death rates have fallen since 1996, during a time when use of LABAs increased fivefold. That's not to say there aren't serious concerns about the drugs' safety, he says.
Harold Nelson, a professor of medicine at the National Jewish Medical and Research Center, led the largest study used by Salpeter, which followed 26,353 patients starting in 1996. That study found a threefold increase in deaths in patients using LABAs, from four to 13, which prompted the FDA's black-box warnings on the drugs. But Nelson says that study participants who were also using inhaled corticosteroids didn't see increased risk. Federal guidelines say LABAs should be used only with corticosteroids, because although LABAs open airways and make people feel better, they don't reduce the underlying inflammation that triggers asthma attacks. Nelson thinks that a likely explanation for poor outcomes with LABAs is that patients weren't treating the underlying inflammation. "They got on the drug, they felt better, they didn't feel the signs of worsening asthma, and they got too sick before they saw anybody," Nelson says.
Patients should stick with the 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; add LABAs if corticosteroids don't provide adequate control. For many people, particularly those with severe asthma, the drugs are very effective, Glassroth says. "We don't have a way of predicting" whose symptoms will grow worse, he says.
The way that patients use LABAs may be partly to blame. Because people feel better almost immediately after using a LABA, doctors worry that they might try to use LABAs as rescue inhalers to open airways during an asthma attack. In its November 2005 health alert, the FDA urged patients to use only short-acting bronchodilators such as albuterol to treat wheezing during attacks. Following the National Heart, Lung, and Blood Institute guidelines for asthma treatment means using one inhaler for corticosteroids, a second for a LABA, and perhaps a third for a rescue bronchodilator. Nelson recommends using Advair, because it combines the LABA with a corticosteroid in one inhaler.