By Tim Drake, PharmD, MBA, BCPS

Assistant Professor of Pharmacy, College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT

Dr. Drake reports no financial relationships relevant to this field of study.

SYNOPSIS: A single dose of inhaled triple therapy improved exacerbations compared to dual therapy in COPD patients.

SOURCE: Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018;378:1671-1680.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for treatment of COPD include inhaled, long-acting beta-agonists (LABA), inhaled, long-acting muscarinic agents (LAMA), inhaled corticosteroids (ICS), and short-acting beta- or muscarinic inhalers (SABA, SAMA).1 Historically, there have been combination inhalers such as LAMA/LABA or ICS/LABA.2 The GOLD guidelines call for a stepped approach to treating COPD, starting with LABA or LAMA therapy and progressing to combination therapy. Eventually, if the patient exhibits severe symptoms or multiple exacerbations, clinicians will add an ICS to current therapy, which will necessitate double or triple therapy.1 Despite the recommendations, the use of ICS in COPD has remained controversial because of the reduced role of inflammation in COPD.

Lipson et al conducted the InforMing the PAthway of COPD Treatment (IMPACT) trial to compare the efficacy and risks of triple inhaled therapy vs. dual inhaled therapy for high-risk COPD patients. This was a Phase III, randomized, double-blind, parallel-group, intent-to-treat, multicenter study of a triple combination of fluticasone furoate 100 mcg (ICS), umeclidinium 62.5 mcg (LAMA), and vilanterol 25 mcg (LABA) in a single inhaler. This single inhaler combination was compared to the dual combination of fluticasone furoate 100 mcg and vilanterol 25 mcg in one inhaler and the dual combination of umeclidinium 62.5 mcg and vilanterol 25 mcg in a single device for 52 weeks. During this time, Lipson et al observed the differences in rates of COPD exacerbations. Secondary outcomes included change in FEV1 readings, change in the St. George’s Respiratory Questionnaire score, time to first exacerbation, time to death from any cause, and all outcomes stratified by an eosinophil count of at least 150 cells per microliter at baseline. The authors recruited patients who were ≥ 40 years of age, presented with COPD symptoms, and demonstrated an FEV1 reading of < 50% of predicted with a history of at least one moderate or severe exacerbation in the previous year, or an FEV1 reading between 50% and 80% and at least two moderate exacerbations or one severe exacerbation in the previous year.

A total of 4,151 patients received triple therapy, 4,134 patients received the ICS/LABA combination, and 2,070 patients received the LAMA/LABA combination. Baseline characteristics were similar across the three groups. On entry, 38% of patients already were on triple therapy with a separate ICS, LAMA, and LABA, 29% were on an ICS with LABA, and 8% were using a LAMA/LABA product. The triple therapy group showed a rate of 0.91 severe or moderate exacerbations per year compared with 1.07 in the ICS/LABA group and 1.21 in the LAMA/LABA group. This resulted in an odds ratio of 0.85 (95% confidence interval [CI], 0.80-0.90) for the triple therapy compared to an odds ratio of 0.75 (95% CI, 0.70-0.81) for ICS/LABA. For secondary outcomes, there was an improvement in FEV1 and the patient questionnaire for the triple therapy group compared to both of the dual-therapy groups. Mortality was lower with the groups that included an ICS. Overall, there was not a significant difference in adverse events. The exception was for pneumonia, which occurred in 8% of patients on triple therapy compared to 7% on ICS/LABA and 6% on LABA/LAMA. This resulted in a hazard ratio of 1.53 (95% CI, 1.22-1.92) in the triple therapy group compared to the LABA/LAMA combination. The authors concluded that triple therapy resulted in fewer moderate-to-severe exacerbations, improved quality of life, and better lung function compared to dual therapy.


The treatment of COPD is problematic because of the progressive nature of the disease and the fact that no medication or combination of medications has been shown to alter the progression of the disease. Medicare is responsible for most costs associated with the treatment of COPD.3 Additionally, most inhalers used to treat COPD are brand name only and relatively expensive. This leads to a high cost burden for Medicare Part D members who are likely to enter the “gap” in coverage if only prescribed one inhaler for COPD per month. Out-of-pocket estimates for two-inhaler therapy is around $1,500 per year and triple-inhaler is almost $3,000 per year.4

The new triple combination of fluticasone furoate, umeclidinium, and vilanterol combines multiple therapy regimens into one inhaler. Although this inhaler is more expensive than dual inhalers, it is less expensive than using a dual inhaler with another single-entity inhaler. This product also may help with patient compliance with the one-puff, once-daily dosing.

This study also proved that it is more efficacious than dual therapy in more advanced COPD patients. The number needed to treat to prevent one moderate-to-severe exacerbation was 3.33 for the triple therapy group compared to the LAMA/LABA and 6.25 for triple therapy compared to the ICS/LABA group. The number needed to harm for pneumonia was 34 for the triple therapy compared to the LAMA/LABA therapy. Considering the cost of a hospitalization for a COPD exacerbation, the use of the triple therapy product in advanced stages of COPD appears to be safe and cost effective.


  1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Am J Respir Crit Care Med 2017;195:557-582.
  2. Global Initiative for Chronic Obstructive Lung Disease. Pocket Guide to COPD Diagnosis, Management, and Prevention: A Guide for Health Care Professionals, 2017 Report. Available online at: Accessed July 19, 2018.
  3. Ford ES, Murphy LB, Khavjou O, et al. Total and state-specific medical and absenteeism costs of COPD among adults aged ≥ 18 years in the United States for 2010 and projections through 2020. Chest 2015;147:31-45.
  4. Tseng C, Yazdany J, Dudley RA, et al. Medicare Part D plans’ coverage and cost-sharing for acute rescue and preventive inhalers for chronic obstructive pulmonary disease. JAMA Intern Med 2017;177:585-588.