Study questions value of certain asthma drugs

A meta-analysis published in the Annals of Internal Medicine last month has re-opened the controversy over long-acting beta agonists in the treatment of asthma.

Clearly, there are two sides to the issue.

According to the authors' conclusions, these drugs increased the risk of severe exacerbations of the disease. They asserted that regulatory agencies should reconsider whether they should remain on the market.

Many experts, however, question the study's methodology and fear its repercussions. Specifically, concerns stemmed from the notion that, since this study was widely reported in the consumer press, patients might react by stopping a treatment that might be helping them.

"Some patients take themselves off it, and they lose some control of their asthma. ... We need to talk about it first," said Sheldon L. Spector, MD, a specialist in allergy, asthma and immunology and a clinical professor of medicine at the University of California, Los Angeles. He also conducts research supported by GlaxoSmithKline into how reaction to these drugs differs on the basis of an individual's genetics.

The authors reviewed trials that compared this drug to placebo and lasted at least three months. All patients were allowed to use short-acting beta agonists as needed, and slightly more than half also were using inhaled corticosteroids. The authors found that the long-acting beta agonists were responsible for one death per one thousand patient-years of use and the majority of asthma deaths annually.

"The message is that long-acting beta-agonists make asthma control worse," said Shelley R. Salpeter, MD, lead author and clinical professor of medicine at Stanford University School of Medicine in California. Two of the other authors were her father, Edwin Salpeter, PhD, the J.G. White Distinguished Professor of Physical Sciences Emeritus at Cornell University in Ithaca, N.Y., and her son Nicholas Buckley, a student at Sequoia High School in Redwood City, Calif. The remaining author was Thomas M. Ormiston, MD, an internist who works with Dr. Salpeter at the Santa Clara Valley Medical Center in San Jose, Calif.

Long-acting beta agonists have been controversial for some time because they appear to reduce the symptoms of asthma without addressing underlying inflammation. For this reason, treatment guidelines recommend against them as first-line therapy. Guidelines generally do endorse their use only in conjunction with inhaled corticosteroids, which are believed to mediate any negative effects while still allowing for the benefits.

"The long-acting beta agonists should really be used in combination with inhaled corticosteroids. Otherwise, the efficacy is likely to be less than it should be, and there's more of a risk," said Akin Ajayi, MD, a pediatric pulmonologist in Orlando, Fla.

For example, a Cochrane Database Systematic Review published in October 2005 found that this combination led to greater improvement in lung function, symptoms and the use of rescue medication among patients with persistent asthma. In addition, a Food and Drug Administration advisory panel in July 2005 concluded that the benefits of these drugs outweighed the risks. The panel recommended that they should stay on the market, although a stronger warning on the label regarding possible adverse events was warranted.

"There is strong and consistent evidence that the combination is the best option, and it's better than doubling the dose of inhaled corticosteroids. It's better than anything else we can do," said Matthew Mintz, MD, associate professor of internal medicine at the George Washington University School of Medicine in Washington, D.C.

Meanwhile, the authors of this paper have defended their analysis, saying it is sound and that the combination of therapies is not as protective as most people think.

"Concomitant corticosteroids do not adequately protect against the adverse effects of [long-acting beta agonists]," Dr. Shelley Salpeter said.

Pointed criticism

But experts complain that this paper took data relating to patients primarily using this drug alone, which long has been regarded as bad practice, and generalized the results to those using these drugs together, which is the preferred strategy.

"The study in and of itself is a good study," Dr. Mintz said. "But some of the conclusions are an over-interpretation and over-extrapolation of the data."

Critics also charge that statistics from the Centers For Disease Control and Prevention, which indicate that asthma-related deaths have been declining since the introduction of these drugs and are now around 4,000 per year, contradict this paper's conclusions. The authors state that deaths from this disease are increasing and are as high as 5,000 per year. They also blame 80% of these deaths on the use of this drug.

"The conclusions didn't make sense at all," said Dr. Spector, and wrote one of several letters to the journal complaining about this paper.

Experts do say, however, that this paper reinforces the need to use these drugs in the right patients.

"If someone is pretty easy to control with one medication, that medication is not a long-acting beta agonist. It's an inhaled corticosteroid," said Barbara Yawn, MD, a family physician and director of research at Olmsted Medical Center in Rochester, Minn. "If a patient is not well-controlled and you know they're really taking their medication, don't assume ... by all means add it."

A spokeswoman for GlaxoSmithKline said the data reported in this study already were reflected on the label but that the company was continuing to monitor the situation.