Popular Asthma Drug’s Use Tied to Death Risk
Heavy use of one of the most common inhaled asthma drugs is associated with a significantly increased risk of dying of asthma, according to new research that suggests that some treatments themselves may help explain the perplexing rise in asthma deaths worldwide.
The study, published today in the New England Journal of Medicine, found that the more heavily a person relied on inhaled drugs called beta agonists, the greater his or her risk of dying of asthma or suffering a near-fatal attack.
“I think doctors and patients ought to be concerned when more than two canisters of beta agonists are used a month,” said Dr. Ralph I. Horwitz, a professor of medicine and epidemiology at Yale School of Medicine and a co-author of the study.
The researchers acknowledged that it is not clear that the drugs themselves are responsible for the increased risk. It is possible that patients who depend more heavily on beta agonists are sicker than others and therefore more likely to die.
Critics of the findings also noted that the greatest risk appeared to be associated with a drug, fenoterol, not available in the United States. They insisted that albuterol, the most common beta agonist in the United States, is safe when used as recommended.
“Patients cannot rely strictly on beta agonists,” said Dr. Michael Kaliner of the U.S. National Institute of Allergy and Infectious Diseases (NIAID). “But they had better not stop (using) them, because they will get in serious trouble.”
Asthma, which is characterized by attacks of breathlessness and wheezing, is believed to affect one in 20 Americans and one in 10 children. Deaths from asthma remain rare but have more than doubled in recent years, from 2,322 in 1970 to 4,868 in 1989. In addition, the rate of death from asthma has almost doubled since the mid-1970s.
Bronchodilator drugs, such as beta agonists, are widely used to relieve the symptoms of acute asthma attacks by widening the airways in the lungs in order to increase air flow. There are three classes of drugs--anticholinergics, methylxanthines and beta adrenergic agonists.
Inhaled beta agonists are the most commonly used asthma drugs in the United States, and albuterol dominates the market. It is sold under the names Proventil, by the Schering-Plough Corp., and Ventolin, by Glaxo Inc.
The study focused primarily on inhaled beta agonists, about which questions had been raised. The researchers did find a similarly elevated risk of death associated with liquid and tablet forms of the drugs, but it was not as statistically significant.
In the study, Canadian and U.S. researchers compared 129 patients with fatal or near-fatal asthma to 655 controls. The group defined a near-fatal event as an episode requiring cardiopulmonary resuscitation, assisted ventilation or other such drastic steps.
The researchers found that for every canister of beta agonist dispensed to a patient per month, the risk of death more than doubled. They said the risk of death increased not only with fenoterol but with albuterol as well as other beta agonists.
“What we found is that there seems to be an excessive use of this drug,” said Samy Suissa, a McGill University associate professor. “We can understand why, because these drugs are so effective that people start relying on them and not on other therapies.”
The problem appears to stem in part from the fact that some patients come to rely too heavily on the drugs. When their condition worsens, they use their inhalers more--rather than have the underlying condition treated with drugs such as corticosteroids.
“What the paper indicates is if you over-rely on them and don’t use other medications when the disease is severe or worsening, you can get into serious trouble,” said Dr. Benjamin Burrows, director of the respiratory sciences center at the University of Arizona.
While the researchers could not say whether the beta agonists were directly responsible for the increased risk of death, they noted that some recent studies have suggested that the drugs may make asthma worse, perhaps by increasing airway sensitivity.
Suissa said his personal feeling is that the increased death risk is attributable to “a little of each”--partly to the fact that people using the drugs tend to be sicker than others, and partly because the drugs can be dangerous in themselves.
Some in the field were skeptical of the results, which expand upon similar 1989 findings from New Zealand. The issue has become a subject of controversy and debate within the medical community in recent months.
Kaliner, for example, questioned the researchers’ methods: The study was based on Canadian health insurance data, not on examination of patients; and it appeared that the patients in the control group were less sick than the others to begin with.
Kaliner said past studies suggest that fenoterol may in fact have problems that can lead to an increased death rate. But he said no studies, besides the new one, had found a similar pattern with albuterol. He doubted whether it exists.
Furthermore, he said the asthma death rate in New Zealand had dropped dramatically in the six months since fenoterol was taken off the market. Albuterol, he said, remains on the market there and the death rate has dropped nevertheless.
Dr. Francis Cuss, vice president for clinical research at Schering-Plough, said his company remains convinced that the drug is safe when used according to the labeling instructions and under the supervision of a physician.
Apparent increases in the asthma death rate have been reported in recent years in the United States, New Zealand, France, Sweden and Great Britain. Under-treatment, overtreatment, emotional turmoil and smog are among the possible influences being studied.
How Bronchodilators Work
Bronchodilator drugs relax muscles surrounding the bronchioles, which are tiny tubes in the lungs.
A. When the bronchioles narrow after contraction of the muscle layer and swelling of the mucous lining, air passage is impeded.
B. Bronchodilators act on the nerve signals that govern muscle activity and encourage muscle relaxation.
Normal bronchioles: Muscle surrounding the bronchioles is relaxed, leaving the airway open.
Asthmatic spasm: Muscle contracts and the lining swells, narrowing the airway.
After treatment: Muscles relax, opening the airway, but the mucous lining remains swollen.
Bronchiole (tube in the lungs)
Alveolar duct
Alveoli (air sacs)
Source: American Medical Assn. Encyclopedia
