Combination Bronchodilators for COPD: A Discussion of the Benefits

Nicholas Gross, MD, PhD


October 17, 2014

Efficacy and Safety of a Fixed-Dose Combination of Indacaterol and Glycopyrronium for the Treatment of COPD: A Systematic Review

Rodrigo GJ, Plaza V
Chest. 2014;146:309-317


Fixed long-acting combinations of both anticholinergic and beta-agonist bronchodilators, not previously available, have been developed. A new fixed combination of glycopyrronium and indacaterol has been extensively evaluated in clinical trials and appears to be nearing US Food and Drug Administration (FDA) approval in the United States. Five phase 3 studies compared the fixed combination of glycopyrronium and indacaterol (Ultibro® Breezhaler®) with each single component or with tiotropium (Spiriva® HandiHaler®).

The trials, which involved 4842 patients with moderate to severe COPD, were randomized, placebo-controlled, and double-blinded and lasted from 3 to 64 weeks. One was a cross-over study. A systematic review of all of these trials showed that lung function, the trough forced expiratory volume in 1 second (FEV1) at 24 hours after a single dose, was significantly improved. There also was a reduction in use of reliever bronchodilation and a significant improvement in quality of life according to a standard chronic obstructive pulmonary disease (COPD) questionnaire called the St Georges Respiratory Questionnaire. These differences applied to the combination vs placebo, vs tiotropium, and vs glycopyrronium (Seebri® Breezhaler®) monotherapy. The safety and tolerability of the fixed combination was equivalent to those of the other treatments. A pooled analysis of the combination vs the beta-agonist monotherapy was not possible.


Bronchodilators, both short- and long-acting versions, are the cornerstone of symptom control in COPD. They also reduce the frequency of acute exacerbations of COPD, which are the events that cause a major amount of the cost of managing the condition.

Patients with severe and very severe COPD, namely those with lung function of 50% or less of predicted values, are likely to have symptoms despite the use of a single bronchodilator, and current guidelines recommend the use of two long-acting bronchodilators if symptoms of COPD are not controlled by a single bronchodilator agent.[1]

Until very recently, healthcare providers and their patients have had to use single bronchodilators of different classes, namely an anticholinergic agent such as tiotropium plus a beta-agonist like formoterol (Foradil®), to control severe symptoms, often taking two inhalers together. Many patients find it less convenient to take two medications as opposed to one, which potentially leads to reduced compliance, a factor that has been shown to lead to worse outcomes.[2] This is one reason why a fixed combination of two bronchodilators, one of each class, in a single device may be of benefit.

A second benefit is that the combination of 2 bronchodilators not only provides more potent bronchodilation, as shown in the trial result reported above, but also avoids the use of a corticosteroid. Those patients who have needed two bronchodilators to control symptoms have until recently been prescribed a long-acting antimuscarinic antagonist (LAMA) and a long-acting beta-agonist (LABA)-corticosteroid combination (eg, Advair® or Symbicort®). Often these patients have no need of a corticosteroid inhalation, nor do they obtain any benefit, but its use exposes the patient to side effects including pneumonia, osteoporosis, and others. The availability of a fixed LAMA-LABA combination makes available a potent 24-hour bronchodilator combination that does not contain a corticosteroid.

A similar fixed combination of an anticholinergic and a LABA indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with COPD was approved by the FDA late in 2013 and is available as Anoro®. The combination described here, which seems similar, is likely to be available very shortly. At least three other such agents, sometimes including the same components as the above, are in late-stage development.



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