Combination Inhalers for COPD: What Are the Benefits?

Nicholas Gross, MD, PhD


October 22, 2015

Efficacy and Safety of Combining Olodaterol Respimat(®) and Tiotropium HandiHaler(®) in Patients With COPD: Results of Two Randomized, Double-blind, ActiveControlled Studies

ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R
Int J Chron Obstruct Pulmon Dis. 2014;9:1133-1144

Fixed-Combination Inhalation Therapies

Chronic obstructive pulmonary disease (COPD) is a common and serious disease and the third most common cause of death in the United States and worldwide.[1] Its symptoms—cough, sputum production, and dyspnea on exertion—are managed with bronchodilators.

Until recently, our therapeutic choices included 12-hour long-acting beta-agonists (LABAs) and a 24-hour long-acting muscarinic antagonist (LAMA) using separate delivery devices. Recently, new fixed combinations of a LABA and a LAMA have become available. Two replicated phase 3 trials of one such combination have been performed and reported.

In this pair of trials, the LAMA component was tiotropium (Spiriva®), a 24-hour agent that has been available as a dry powder inhalation (HandiHaler®) for COPD for some years. The LABA component was olodaterol (Striverdi®), a 24-hour bronchodilator delivered by the Respimat® "soft mist" delivery device. Olodaterol was approved for COPD as a monotherapy in 2014. Both trials examined the safety and efficacy of adding olodaterol or a matching placebo to tiotropium.

The trials were 12 weeks in duration, randomized, and double-blind in format. The patients (a total of 2267) had moderate-to-severe COPD. All were current or former cigarette smokers. The primary efficacy endpoint was improvement in lung function at 12 weeks, and both trials showed that the LABA/LAMA combination resulted in statistically greater improvement than the LAMA/placebo combination.

Quality of life, as determined by the St George's Respiratory Questionnaire, was statistically but not clinically better with the combination treatment. Adverse events were similar among the treatment groups in both trials. Acute exacerbations of COPD, at a mean rate of about one per patient per year, occurred at similar rates in each group. The authors concluded that the combination of olodaterol and tiotropium provided improvements in lung function over tiotropium alone without an increase in adverse events.


Combinations of the short-acting beta-agonist albuterol (Combivent®) and the short-acting antimuscarinic ipratropium (DuoNeb®) have been very widely and successfully used for many years. However, the relief they provide is relatively brief in duration. The also do not provide the same long-term benefits, such as reductions in the rate of acute exacerbations, that long-acting agents have been shown to provide.[1]

Long-acting agents (those of 12 or 24 hours duration) are preferred by patients, result in good compliance, and provide such benefits as reductions in acute exacerbations, reductions in hyperinflation and dyspnea, and improvements in exercise tolerance.[2,3] In the past few years, clinicians have sought agents with longer durations of action—24-hour duration is most preferable, both for the clinical benefits mentioned above and also because patients would be less likely to skip doses.

Clinicians have also sought fixed combinations of bronchodilators for the increase in symptom relief they would provide. Because anticholinergic agents and beta-agonists act on different receptors located in different airway sites, combinations of LABAs and LAMAs can be expected to result in more bronchodilation, as these trials illustrate. Fixed combinations of two agents delivered in the same device have additional benefits, including patient convenience and compliance. In the present replicated trials, the two drugs were delivered separately using different delivery devices. It is probable that the sponsors plan to conduct similar trials with fixed combinations delivered with a single device (most likely the Respimat "soft mist" inhalation device).

The trend toward fixed combinations of two or more therapies can be seen in the management of many common disorders, such as diabetes, hypertension, infectious diseases, and cancers. Similarly, inhalation of fixed combinations is becoming the standard in the management of airway diseases. The availability and chemical compatibility of several new and existing LABAs and LAMAs, some of which are off-patent, make it possible for pharmaceutical companies to put together many fixed combinations with confidence that they will be safe and effective.

Anoro®, GlaxoSmithKline's fixed combination of their LABA vilanterol and their antimuscarinic umeclidinium, was approved by the US Food and Drug Administration and made available for COPD last year. In the absence of head-to-head trials, it is not possible to determine whether one such combination is better than another. Several similar fixed combinations are in various stages of development, ensuring that, in the near future, several will be available for routine use. Among them will be dry powder, metered-dose, and nebulized solutions; 12-hour and 24-hour preparations; and the holy grail of inhalation therapy for COPD: LAMA-LABA-inhaled corticosteroid combinations.



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