Initiation of Triple Therapy in Chronic Obstructive Pulmonary Disease

Stephanie Keller, Pharm.D., Coborn’s Pharmacy / CHI St. Gabriel’s Health Family Medical Center

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 guidelines provide recommendations for the pharmacological management of COPD based on an individualized assessment of symptoms and exacerbation risk. Long-acting muscarinic antagonists (LAMAs) and long-acting beta2-agonists (LABAs), alone or in combination, are preferred therapeutic options for patients with COPD. Triple therapy with a LAMA, LABA, and inhaled corticosteroid (ICS) has previously been reserved for patients with severe COPD and a high risk of exacerbations. The updated 2019 GOLD guidelines outline new recommendations for initiating add-on ICS therapy in patients with COPD exacerbations based on blood eosinophil count. Although these evidence-based recommendations exist for the treatment of COPD, studies suggest that real-world treatment patterns do not always follow clinical practice guidelines.

Objective: The purpose of this study was to (1) measure the time from COPD diagnosis to the initiation of monotherapy with a LAMA or dual therapy with LAMA/LABA or LABA/ICS, (2) estimate the time to initiation of triple therapy, and (3) identify factors contributing to the progression to triple therapy.  

Study Design: This study was a retrospective analysis of patients with COPD who initiated LAMA monotherapy or dual therapy with LAMA/LABA or LABA/ICS between July 1, 2010 and March 31, 2013.  The Humana research database was utilized to obtain healthcare claims data for these fully insured patients with commercial or Medicare Advantage Prescription Drug (MAPD) insurance plans. Patients were required to have a diagnosis of COPD, which was identified using ICD-9 codes for chronic bronchitis, emphysema, and chronic airway obstruction. Patients aged 40 years or older with COPD as a diagnosis for at least one hospitalization claim, one emergency department claim, or one medical claim for an office visit in the year prior to study initiation were included. Patients were excluded if claim records indicated prior use of LAMA, LAMA/LABA or LABA/ICS, those with comorbid respiratory-related conditions, those who switched plan type from commercial to MAPD, or those who were contractually excluded from research. The study was sponsored by GlaxoSmithKline, who also played a role in the study design, data analysis, data interpretation, and writing of the manuscript.

Results: There were 13,541 patients with a confirmed diagnosis of COPD. Of these patients, 4000 initiated LAMA monotherapy, 8207 initiated LABA/ICS dual therapy, and 77 initiated LAMA/LABA dual therapy at the beginning of the study. The mean time from COPD diagnosis to initiation of therapy was 178 (± 134) days for LAMA monotherapy, 185 (± 130) days for LABA/ICS dual therapy, and 252 (± 124) days for LAMA/LABA dual therapy. Of these patients, 28% receiving LAMA monotherapy and 20% receiving dual therapy (LAMA/LABA or LABA/ICS) progressed to triple therapy. Triple therapy was initiated after a mean of 367 (± 362) days for those receiving LAMA monotherapy, 393 (± 366) days for those receiving LABA/ICS, and 617 (± 454) days for those receiving LAMA/LABA. Exacerbations occurred within the 60 days prior to initiating triple therapy in approximately 22% of patients receiving monotherapy or dual therapy. When considering the 12 months before initiating triple therapy, exacerbations occurred in about 50% of patients. Factors that were significant predictors of progression to triple therapy included race/ethnicity, geographic region, discontinuation of therapy, smoking history, use of LAMA monotherapy, and concomitant use of ICS, xanthenes or short-acting beta2-agonists.

Conclusions: In this study, 23% of patients with COPD progressed to triple therapy within 12 months of starting treatment with monotherapy or dual therapy. Only 50% of these patients had exacerbations in the year prior to progressing to triple therapy. Several factors were identified that predicted progression to triple therapy. The authors suggested that these factors may help identify patients that could benefit from earlier intervention with triple therapy. The study indicated that those who discontinued therapy, had a smoking history, received LAMA monotherapy, or used concomitant xanthenes or short-acting beta2-agonists were more likely to progress to triple therapy. However, additional studies are necessary to determine whether time to initiation of triple therapy is associated with patient outcomes.

Although there were various limitations to the study design, the treatment patterns identified do not appear to align with current practice guidelines. The majority of patients in this analysis were initiated on ICS/LABA dual therapy after COPD diagnosis. Furthermore, the 2019 GOLD guidelines take into account that several recent studies have demonstrated that blood eosinophil counts predict the magnitude of the effect of ICS add-on therapy in preventing future exacerbations. Therefore, these guidelines emphasize the importance of evaluating blood eosinophil count along with exacerbation risk when considering triple therapy with ICS.

Key Point: The results from this study highlight the discrepancy between clinical practice guidelines and real-world treatment patterns in the pharmacological management of COPD. Pharmacists have the opportunity to intervene and promote the utilization of evidence-based treatment recommendations. With the expansion of available LAMA, LAMA/LABA, LAMA/LABA/ICS inhalers, it is also important to educate providers on these new medications.


  1. Lane DC, Stemkowski S, Stanford RH, Tao Z. Initiation of triple therapy with multiple inhalers in chronic obstructive pulmonary disease: an analysis of treatment patterns from a U.S. retrospective database study. J Manag Care Spec Pharm. 2018 Nov;24(11):1165-1172. doi: 10.18553/jmcp.2018.24.11.1165.

  2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2019 report. Accessed February 8, 2019.