Dual therapy strategies for COPD: The scientific rationale for LAMA & LABA

COPD is a leading cause of death throughout the world. Chronic exposure to inhaled irritants-commonly cigarette smoke-induces an inflammatory response in the lungs that develops into COPD.  Despite the variety in clinical subtypes, (bronchitis, emphysema, and frequent exacerbations) there is no difference in GOLD guideline recommendations for therapeutic interventions among groups.

Bronchodilators are the cornerstone of therapy for all patients with COPD.  Muscarinic receptor antagonists block the effects of the parasympathetic nervous system. Beta receptor agonists stimulate the receptors on the smooth muscles of the airways. Both mechanisms relax the smooth muscle tone of the respiratory tract and result in dilation of the airways. Each class of medication is commonly used as monotherapy for treatment of COPD. Studies investigating the short acting bronchodilator effects of albuterol and ipratropium in combination have demonstrated improvements in dyspnea, lung function, and use of rescue medication without compromising safety.

Patients currently prescribed a single long-acting bronchodilator who remain symptomatic may benefit from dual therapy with a long acting beta agonist (LABA) and a long acting muscarinic antagonist (LAMA). This combination has the potential to provide added efficacy for treatment of COPD due to complimentary mechanisms. The beneficial synergistic effects of dual therapy may be achieved at lower doses than required for monotherapy, which may reduce associated adverse effects.

There is a growing group of LAMA/LABA combination therapies in development. Investigations into the risks and benefits of LAMA/LABA therapy have demonstrated benefits that include:

o A reduction in dyspnea

o Improved health-related quality of life scores

o Improved lung function, as assessed by FEV1

o Reduced use of rescue medication. 

The impact of this therapy on exacerbation frequency has not been fully elucidated, although some studies have shown a trend. Because the baseline rate of exacerbation is low in inclusion groups for studies of LAMA/LABA dual therapy, the studies are not powered to specifically address exacerbation as a study endpoint.  The GOLD guidelines recommend the use of inhaled corticosteroids (ICS) in patients who have a history of acute exacerbations. However, studies assessing prescriber adherence to the GOLD guidelines have demonstrated the frequent use of ICS in patients without such a history. Evidence from ILLUMINATE suggests that switching patients without a history of exacerbations from ICS/LABA therapy to LAMA/LABA therapy may improve symptoms. This may allow patients to avoid steroid treatment and its associated adverse effects.

Regarding onset of acute exacerbations, WISDOM demonstrated non-inferiority of dual LAMA/LABA therapy in patients who stepped down from triple therapy (ICS/LAMA/LABA) compared with patients who remained on triple therapy.

Until the clinical subtypes of COPD are better understood, indication for dual therapy with LAMA/LABA combinations is best described by the GOLD guidelines-patients with symptomatic mild to moderate COPD and a low risk of exacerbation.  When selecting a product as therapy for a patient, in addition to the guidelines, drug interactions, adverse effects, patient education, and adherence must also be considered.

Adherence to medication is a problem among patients with COPD. Non-adherence is increased with complexity of a treatment regimen, difficulty of inhaler use, delay in symptomatic relief, and lack of patient education. With the multitude of devices available, it is critical to provide patients with proper counseling of inhaler use and to select a product with a delivery device that the patient can properly manipulate so that the needed dose can be delivered.  Selection of a single combination LAMA/LABA inhaler over two bronchodilator inhalers also has the potential of simplifying a therapy regimen and reducing cost. 

Treatment optimization requires tailoring a patient’s drug regimen to best address his or her clinical, financial, and physical needs. The dual LAMA/LABA combination therapies coming to market increase the available options.

Kathryn Wheeler PharmD, BCPS, is an associate clinical professor of pharmacy practice at the University of Connecticut, School of Pharmacy.