BETHESDA, MD 26 October 2012—A recently published meta-analysis highlights the tension between FDA recommendations and federal clinical guidelines for the treatment of patients with asthma.
FDA in 2010 recommended that patients treated with inhaled corticosteroids plus a long-acting β-adrenergic agonist (LABA) should stop using the LABA once asthma symptoms are controlled. The goal, according to the agency, is to use LABAs for "the shortest duration of time required to achieve control of asthma symptoms."
The recommendation was added to a boxed warning in the labeling for LABAs and reinforced in a risk evaluation and mitigation strategy (REMS) program for that class of drugs. According to FDA, the agency acted in response to evidence that LABAs increase the risk of exacerbations of asthma, hospitalization, and death.
Clinical guidelines for the management of asthma from the National Heart, Lung and Blood Institute's National Asthma Education and Prevention Program (NAEPP) were last updated in 2007.
The NAEPP guidelines give equal weight to increasing the inhaled corticosteroid dose or adding a LABA for the control of moderate persistent asthma or asthma that is not well controlled by a low-dose corticosteroid. Both the NAEPP guidelines and FDA recommend against LABA monotherapy for the control of asthma.
For patients with severe persistent asthma that has not been well controlled, combination therapy with a LABA and an inhaled corticosteroid is the preferred treatment, according to the NAEPP guidelines.
The guidelines ask clinicians to consider the risks and benefits of stopping LABA therapy in patients whose asthma has been well controlled for several months. This time frame is seemingly at odds with FDA's call for a more immediate cessation of the therapy.
After the labeling changes for LABAs were implemented, two experts who helped develop the NAEPP guidelines published a report that emphasized the conflict over the timing of LABA discontinuation. The report also noted that no definitive guidance exists on how to best halt LABA therapy.
The new meta-analysis, published online August 27 by the Archives of Internal Medicine, examined data from studies involving patients whose asthma was well controlled with a LABA and an inhaled corticosteroid.
That report found that discontinuing a LABA while maintaining inhaled corticosteroid therapy produced no discernible benefits but led to a decrease in quality of life and poorer asthma control. Patients who stopped taking a LABA had fewer symptom-free days and a greater use of rescue bronchodilators and oral corticosteroids.
Dennis Williams, associate professor and vice chair for professional education and practice at the University of North Carolina's Eshelman School of Pharmacy, said the spate of conflicting guidance about asthma therapy "puts people in clinical practice in quite a quandary."
Williams, the American Pharmacists Association's representative on the coordinating committee for the NAEPP guidelines, said inhaled corticosteroids have a good safety record and pose fewer risks than oral prednisone. But he said patients and prescribers still worry about the dose-related adverse events associated with inhaled corticosteroids.
These adverse events include oral candidiasis, hoarseness, slowed growth in children, and osteoporosis.
"What we try to tell patients is, 'We're going to make sure you're on the lowest dosage of inhaled steroids that it takes to control your condition,'" Williams said.
But that dosage may need to be increased if a patient whose asthma is controlled by combination therapy stops taking a LABA.
"If you go that route, you're exposing a lot more people to higher doses of inhaled steroids. And in fact, in head-to-head studies about those two strategies, the combination is associated with better asthma control," he said.
LABAs come in inhalers that deliver one specific dose with each use, and all have FDA-approved labeling limiting use to twice daily at most. Inhalers containing a LABA and a corticosteroid have different dosage strengths of the corticosteroid component but just one strength of the LABA.
Kathryn Blake, senior research scientist at the Nemours Children's Clinic's Center for Pharmacogenomics and Translational Research in Jacksonville, Florida, and ASHP's representative on the coordinating committee for the NAEPP guidelines, said this means there's no way for patients to decrease their LABA dosage; they are either taking the available dose or they are off the medication.
She noted that simply decreasing the frequency of dosing would render the LABA ineffective and expose patients to the risks of the drug but not its benefits.
Unfortunately, she said, this scenario occurs in clinical practice, because many patients take their asthma medications less often than prescribed. Studies have long shown low rates of adherence—sometimes less than 50%—to asthma therapy.
FDA last year announced that the manufacturers of LABAs are required to conduct large clinical trials to investigate the safety of combination therapy compared with inhaled corticosteroid monotherapy for asthma. Results from the study are expected in 2017.
Nemours Children's Clinic is participating in a different multicenter clinical trial that will compare the effectiveness of inhaled corticosteroid therapy with or without a LABA. The 56-week, 450-patient study will compare a combination regimen with standard LABA–inhaled corticosteroid therapy, a reduced inhaled corticosteroid dose plus continued use of a LABA, and maintenance of the inhaled corticosteroid dose plus discontinuation of a LABA.
Blake said that because the August meta-analysis covered only studies lasting 12–16 weeks, longer-term adverse outcomes, such as emergency room visits and hospitalizations, could not be reliably determined. The new study at Nemours should be able to better assess these outcomes.
"It will be a cleaner study than the ones that are out there," Blake said. The expected completion date for the study is June 2015, according to a summary on ClinicalTrials.gov.
Williams said that for now, clinicians need to examine the population-level guidance from FDA and NAEPP and then individualize therapy for each patient.
Blake likewise said that clinicians "are clearly left with following their own assessment of the individual patient and the risks that they may have if they were to stop treatment."
"Probably the best thing that clinicians can do, if they do decide to take them off treatment, is to have very close monitoring just to make sure that the patient is not going to get into trouble and have a worse outcome," she said.