Combination Therapies for COPD

Nicholas Gross, MD, PhD


May 07, 2015


Tiotropium and Olodaterol Fixed-dose Combination Versus Mono-components in COPD (GOLD 2-4)

Buhl R, Maltais F, Abrahams R, et al
Eur Resp J. 2015:45:969-979

Chronic obstructive pulmonary disease (COPD) is a progressive disorder that affects 15.7 million adults and causes about 135,000 deaths per year in the United States (2013 data).[1] We have no treatments that alter the clinical course of COPD other than smoking cessation and, for the small group of patients who have persistent hypoxemia, long-term oxygen therapy.[2]

Treatment is therefore directed toward relief of symptoms and a reduction in the incidence of acute exacerbations. Within the past decade, major advances in management have been made in the development of new bronchodilators with longer activities and more effective delivery devices.

Fixed combinations of agents with different actions are also being developed. One such agent, which was the subject of this recent trial, is not yet approved but shortly will be submitted to the US Food and Drug Administration (FDA) for approval in United States. It is the combination of the long-acting anticholinergic bronchodilator tiotropium and the long-acting beta-adrenergic agent olodaterol. The trial of this combination has been reported and demonstrates the range and extent of benefits that can be obtained with fixed-dose combinations of bronchodilators.

In a randomized controlled trial, 5162 patients from 25 countries who had moderate to very severe COPD received either tiotropium alone, olodaterol alone, or their fixed combination for 1 year. The agents were administered once daily by a soft-mist aerosol nebulizer, known as the Respimat® (Boehringer Ingelheim; Ridgefield, Connecticut). Co-primary endpoints were lung function (FEV1 during the first 3 hours after administration), trough FEV1 (24 hours after a dose and immediately before the next dose), and score on a health status instrument (St George's Respiratory Questionnaire [SGRQ]).

The results showed that FEV1 over the first 3 hours of combination therapy resulted in clinically and statistically significantly more bronchodilation than either tiotropium or olodaterol monotherapy alone. Similarly, trough FEV1 was statistically greater than with either tiotropium or olodaterol monotherapy. At 24 weeks, the SGRQ score in all groups was significantly better than their baseline measurements, and the SGRQ score of the combination therapy group was better than that of the monotherapy groups.

The incidence of adverse events, serious and otherwise, was similar across all groups, acute exacerbations of COPD being the most common. Most adverse events were of mild or moderate severity, and only between 6.0% and 7.1% of adverse events were considered to be treatment-related.

Bearing in mind that both olodaterol and tiotropium have been individually shown to be safe and effective in COPD, the fixed-dose combination of these two agents nevertheless shows greater efficacy than either agent alone, without the cost of an increase in adverse events.


This study is representative of several studies[3] in which fixed-dose combinations of maintenance therapies are being developed for COPD.[2] The first 24-hour combination of a beta-agonist and an anticholinergic agent was approved for COPD by the FDA in December 2013.

Long-acting bronchodilators of both the beta-agonist and anticholinergic varieties have been available and approved as monotherapies for COPD for a decade or more. It has not been shown, or tested, whether these very potent bronchodilators decrease mortality. What is the benefit, and why are these combinations being developed? Adherence to long-term therapy is an issue in COPD; this is largely because patients with COPD typically have multiple comorbidities for which they need to take multiple therapies.

In the present study, 86% of patients had at least one diagnosed comorbidity. The convenience of taking one treatment for their COPD is likely to improve adherence. In addition, a combination therapy ensures that patients who take their therapy receive both agents; they cannot take just one. Most of the new combination therapies have a 24-hour duration of action—a further convenience for most patients.

The agents in an adrenergic/anticholinergic combination have different pharmacologic actions and work on different receptors, so their benefits are additive. A further advantage is that this type of combination does not contain a corticosteroid. In COPD, corticosteroids should only be used when the patient has experienced acute exacerbations. Until very recently, the only long-acting fixed-dose combinations for COPD contained a corticosteroid as one of their components. In my experience, for most patients with mild or moderate disease, the corticosteroid component was unnecessary and served only to expose them to possible steroid-related adverse events.

The standard paradigm for COPD management now begins with a short-acting bronchodilator to be taken as necessary; if this is insufficient to control symptoms, it should be complemented with a long-acting bronchodilator monotherapy, either an anticholinergic or a beta-adrenergic agent, to be used on a maintenance basis. If the patient's symptoms are not thus controlled, then a fixed-dose combination of a beta-adrenergic and an anticholinergic agent can be prescribed. The short-acting bronchodilator should continue to be used for "breakthrough" dyspnea. The steroid-containing combinations should be used only when the patient has experienced an acute exacerbation or when the patient's condition appears to have an asthmatic component.

The fixed-dose combination of agents with different actions, such as the tiotropium/olodaterol agent discussed here, is probably a transition to a triple agent—one that contains fixed doses of anticholinergic, beta-adrenergic, and corticosteroid components. Trials of such agents are in progress.


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