Lung experts from Johns Hopkins and elsewhere are calling on physicians to suspend the routine use of potent heartburn medications in asthmatics solely to temper recurrent attacks of wheezing, coughing and breathlessness.
Calling the longstanding practice "ineffective" and "unnecessarily expensive," the experts say there is no benefit from using so-called proton pump inhibitors in the absence of the stomach upset. The condition plagues 5 million asthma sufferers in the United States, of whom half (or 2.5 million) have what is known as "silent" reflux, and lack the characteristic symptom of heartburn from the backup of acid into the esophagus.
Overall, as much as $10 million is spent each year in the United States treating gastroesophageal reflux disease in asthmatics struggling to control their lung symptoms.
The scientists base their call on their latest research, believed to be the most extensive monitoring ever done of how well the drugs, first made available in the 1990s, tame respiratory flare-ups in asthmatics for whom steroid therapy and other drugs have already failed.
Senior study investigator and Johns Hopkins pulmonologist Robert A. Wise, M.D., says the results dispel some common assumptions about the disease, offering the first solid evidence against silent acid reflux as having any significant role in poor asthma control.
Reporting in the New England Journal of Medicine online April 9, researchers at 20 medical centers in the United States collected detailed health reports on 412 men and women who still have asthma symptoms despite drug therapy. Half took daily doses of the most commonly used proton pump inhibitor -- 80 milligrams of esomeprazole (Nexium) -- while the rest received a placebo.
After six months, the average number of self-reported episodes of breathlessness -- those that required use of inhalers, and which stirred nighttime awakenings or led to visits to the hospital emergency room -- were the same for both groups (at 2.5 and 2.3 per person per year, respectively), disproving any drug benefit. Moreover, researchers saw no improvements in overall health or other quality-of-life measures, such as how much time study participants spent going out with friends, or how well they performed their work or kept pace with their college coursework.
"The bottom line here is that proton pump inhibitors do not improve control of asthma on their own," says Wise, a professor at the Johns Hopkins University School of Medicine.
Four out of 10 asthma sufferers, he notes, are struggling to control their asthma, whether or not they have symptoms of gastroesophageal reflux disease, or GERD.
Patients can easily confuse their heartburn symptoms with their asthma symptoms, which Wise says only adds to the difficulty in deciding about which treatment to use.
Yet surveys also show that as many as 65 percent of these people take proton pump inhibitors anyway, because doctors have presumed that it may improve their asthma.
But until now, no study had closely monitored asthmatics shown to have the silent form of GERD by taking precise measures of esophageal pH acidity levels, in which only patients free of any heartburn were treated. "Our recommendation to physicians is that these drugs should only be considered for asthmatics who have symptoms of gastroesophageal reflux, at least twice a week," says Wise.
In the study, each asthmatic participant kept a daily diary of lung health. Researchers supported these records with two tests of lung function, plus a test to see if airways constricted or not in response to chemical irritants. These results were combined with two surveys that measured illness-related behavior changes, such as not going out to parties or cutting back on physical exercises due to fear of an asthma attack.
Results showed that none of these factors changed markedly between the esomeprazole-treated group or the placebo group. Three participants taking esomeprazole had asthma attacks serious enough to warrant a stay in the hospital; and four in the placebo group had attacks that required hospitalization - numbers that researchers say, statistically, are the same.
Besides asthma attacks, study participants were surveyed for actual backup of stomach acid. In the test, probes were slid through the nose, down the throat and into the esophagus to measure acidity levels. Some 40 percent of participants were found to have gastroesophageal reflux, recorded as prolonged periods of severe acidity in the esophagus, as measured by a pH acidity level of less than 4 lasting more than two hours throughout the day.
But even among this group of asthma sufferers, the study showed that proton-pump inhibiting drugs offered no improvements in how fast people could blow air out of their lungs. Drug therapy also did not help open the airways in patients tested with bronchodilator medications.
According to study co-investigator Janet Holbrook, Ph.D., M.P.H., a "significant outlay" of money goes toward treating asthma and related gastric reflux -- proton pump inhibitors cost on average between $150 and $180 per month for the half dozen most common brands. Probe tests used to gauge the severity of the heartburn can cost as much as $1,200.
"It's only when you conduct placebo-controlled clinical trials that you have a fair test of what works best and what does not in controlling asthma," says Holbrook, an associate professor at Johns Hopkins Bloomberg School of Public Health. "These drugs are safe and work well for controlling heartburn and healing acid irritation in the esophagus, but they simply do not pass the efficacy test for millions of people with this lung disease."
Wise says the study results provide important evidence for the National Asthma Education and Prevention Program, an expert group coordinated by the National Heart, Lung and Blood Institute and the National Institutes of Health, to consider when it next updates its evidence-based treatment guidelines.
He says the research team has already begun testing proton pump inhibitors in children with asthma. Children, he notes, have a shorter esophagus than adults, making it easier for stomach fluids to back up and into the throat and get sucked into the lungs. This, he says, could explain why children may benefit from these drugs while adults do not.
Funding support for the study was provided by the National Heart, Lung and Blood Institute, a member of the National Institutes of Health, and by the American Lung Association. Johns Hopkins is the coordinating center among 20 Asthma Clinical Research Centers, all funded by the American Lung Association as part of a dedicated effort to conduct clinical trials in the disease that have a practical impact on people's lives.
The esomeprazole drugs used in the study was provided by its manufacturer, AstraZeneca, based in Wilmington, Del. Wise is a paid consultant to AstraZeneca. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
Other researchers involved in writing the report were John Mastronarde from The Ohio State University Medical College in Columbus; Nicholas Anthonisen from the University of Manitoba in Winnipeg, Canada; Mario Castro from Washington University in St. Louis; Frank Leone from the University of Pennsylvania School of Medicine in Philadelphia; and Gerald Teague from Emory University School of Medicine in Atlanta.
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Video clips of Wise and a patient commenting about the study can be found online April 8 at www.hopkinsmedicine.org.