Role of Anti-Muscarinic for Asthma Revealed in Meta-Analysis

Diana Sobieraj, PharmD

A meta-analysis of studies adding a long-acting muscarinic antagonist (LAMA) to treatment with an inhaled corticosteroid finds less risk of asthma exacerbation than with placebo add-on, but not less than with combinations of corticosteroid and long-acting beta-agonists (LABA).

Diana Sobieraj, PharmD, Department of Pharmacy Practice, University of Connecticut School of Pharmacy, and colleagues point out that current treatment guidelines which recommend stepwise escalation with addition of LABA to inhaled corticosteroids have not accounted for the utility of LAMA.

"If control remains suboptimal (after the LABA addition), options include further increasing the inhaled corticosteroids dose and adding adjuncts such as biologics or oral corticosteroids," researchers wrote. "Such therapies expose patients to systemic effects of drugs and thus carry the risk of more significant adverse effects."

In an editorial accompanying the meta-analysis, Jerry Krishnan, MD, PhD, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois, Chicago, IL and David Au, MD, MS, Health Services Research and Development Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA concur with the need to update guidelines to include LAMA.

"Almost 11 years have elapsed since the publication of the 2007 Expert Panel Report 3 (EPR-3) guidelines on asthma," Krishnan and Au noted.

They suggest that the current meta-analysis could inform a necessary update.

"Such changes to the EPR-3 guidelines would help to harmonize the approval by the FDA for inhaled tiotropium and the clinical guidelines in the United States," Krishnan and Au wrote.

Sobierai and colleagues evaluated 15 randomized controlled trials involving 7,122 subjects, including 789 adolescents, which met a number of criteria. These included tracking asthma exacerbations by such conditions as systemic corticosteroid use, hospitalizations, emergency department visits, intensive care or intubation, mortality (all-cause or asthma specific), and spirometry. The studies were also to determine asthma control via the Asthma Control Test (ACT) or Asthma Control Questionnaires (ACQs), and by assessing health care utilization through additional use of medications or health resources related to the intervention.

The meta-analysis compared outcomes from adding either a LAMA, a placebo, or another controller medication to treatment with corticosteroids; and compared use of a "triple therapy" of LAMA, corticosteroids and LABA to corticosteroid and LABA combination.

Sobierai and colleagues found that the addition of LAMA to inhaled corticosteroids maintenance therapy, in patients 12 years and older, was associated with lower exacerbation risk and improved spirometry values compared to addition of placebo, but not compared to the corticosteroid and LABA combination.

"This systematic review did not find sufficient evidence that adding LAMA to inhaled corticosteroids in this population was associated with improvements in clinical outcomes vs adding LABA," Sobierai and colleagues wrote.

They did find that "triple therapy" was associated with some improved outcomes such as spirometry compared to LABA and inhaled corticosteroids, but not with reduced risk for asthma exacerbation.

Krishnan and Au pointed out that while there were too few children in the analyzed studies to assess outcomes in subjects younger than 12 years, subsequent trials have supported the FDA approval in 2017 of inhaled tiotropium for long-term, once-daily, maintenance treatment of asthma in patients 6 years or older.

"Another limitation of the report of the report is that the analyses focused on efficacy and did not examine the potential for harm or the relative costs of different regimens," Krishnan and Au noted.

The study, "Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma," was published online in JAMA last month.