The US Food and Drug Administration and Long-Acting Beta-2-Agonists: The Importance of Striking the Right Balance Between Risks and Benefits of Therapy?
Lemanske RF, Busse WW
J Allergy Clin Immunol. 2010;126:449-452
Following the introduction of long-acting beta-agonists (LABAs) and their approval for use in asthma and chronic obstructive pulmonary disease (COPD), questions about their safety arose. Specifically, there were concerns about a possible increase in asthma mortality associated with the use of salmeterol in a United Kingdom postmarketing study. A similar study (SMART - Salmeterol Multicenter Asthma Research Trial) was subsequently carried out in the United States and this appeared to confirm a small but statistically significant increase in mortality in patients with asthma who received salmeterol compared with a similar control group who did not. However, the study design left room for questions about the validity of the result. Following hearings on the subject, the Division of Pulmonary and Allergy Products of the US Food and Drug Administration (FDA) announced updated recommendations that included label changes and black box warnings for the use of all LABAs. The changes specified that LABAs:
should not be used in patients "whose asthma is adequately controlled with a low- or medium-dose inhaled corticosteroid";
were "contraindicated for asthma in patients of all ages without concomitant use of an asthma-controller medication such as an inhaled corticosteroid";
"should be discontinued, if possible, once asthma control is achieved, maintaining the use of an asthma-controller medication, such as an inhaled corticosteroid"; and
that "a fixed-dose combination product containing a LABA and an inhaled corticosteroid should be used to ensure compliance with concomitant therapy in pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid."
Because some of these requirements were of considerable concern to practitioners and, specifically, to asthma and allergy specialists, a great deal has been written and voiced on the subject. The present citation is a thorough analysis of the issues. The issue of most concern is the recommendation that the LABA be discontinued when asthma control is established. Lemanske and Busse state that this recommendation runs counter to expert opinion and guidelines and no evidence supports the recommendation. Specifically, they ask, what are the criteria for asthma control in the context of withdrawing the LABA? How long should one wait after asthma has been "controlled" before discontinuing the LABA? How, logistically, does one discontinue the LABA -- abruptly or gradually? The FDA's statement does not provide the clinician with guidance on how to implement these recommendations in practice. The Expert Panel Report-3 considered the risk of long-term corticosteroid use to outweigh that of LABA use and therefore recommends that the steroid, rather than the LABA, be reduced when control is achieved. The concerns apply particularly to patients with severe asthma in whom loss of asthma control and risk for a recurrent severe asthma exacerbation could be most serious.
The FDA's statement has come as a surprise to many, and the present publication by 2 highly respected and experienced asthma specialists is probably the clearest and most authoritative statement of the profession's concern. Nearly everyone would agree that LABA monotherapy is not optimal treatment for asthma because, regardless of whether LABAs are inherently dangerous, patients might be tempted to overuse them when they have an exacerbation of asthma instead of taking corticosteroids, thus perhaps delaying the appropriate treatment. However, present guidelines do not recommend LABA use without a concomitant anti-inflammatory agent at any management step.
The most concern arises over the recommendation that the LABA be withdrawn when an acute asthma event has been controlled by adding an LABA to anti-inflammatory treatment. There is ample evidence that when the patient's asthma is not well controlled with moderate doses of an anti-inflammatory agent alone, the most effective step-up therapy is the addition of an LABA. This applies both to children aged 6 years and above as well as to adults. However, almost no studies exist to guide the clinician in how to step down therapy, and most clinicians would feel that if the addition of an LABA was needed to control the asthma, it would be inappropriate to subsequently withdraw it. Indeed, there are studies showing that discontinuation of an LABA after achieving asthma control has been followed by a loss of control.[11,12]
It is understood that the FDA's intention was to minimize the risk associated with maintenance LABA use. However, clinicians have to balance that risk against the risk of not using a LABA. That calculus seems not to have been addressed. The risk for mortality in the SMART study was approximately 1 in 700 patients. What is the risk of withdrawing an LABA after bringing an asthma episode under control with an LABA-steroid combination? Could it not be greater than the risk of maintaining the LABA-steroid combination? That question has not been answered.
Clinicians are almost unanimous in the opinion that asthma control has greatly improved since the introduction of LABAs in the 1990s. Patients and their advocates expressed a similar opinion at the FDA hearings on the subject in December 2008. Epidemiologic data show that asthma-related mortality in the United States, having steadily increased in the second half of the 20th century, has declined since the introduction and widespread use of the fixed LABA-steroid combinations for maintenance treatment in the 1990s.
Clinicians are not only concerned about losing the therapeutic benefits of LABAs. They also wonder whether it is possible that managed care and pharmacy plans will now decline to reimburse for maintenance LABA prescriptions. Do caregivers face malpractice litigation if patients with asthma have any adverse events while on maintenance LABA? As the authors state, "These recommendations ...could alter the landscape...for asthma management." The best policy, as usual, is to treat patients individually, use best judgment to select the treatments that best suit each patient's needs, and document the reasons for all decisions in the patients' charts.
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