The Problem

A 74-year-old man with a history of type 2 diabetes, coronary artery disease, hypertension, and chronic obstructive pulmonary disease presents to your office following evaluation and treatment in the emergency department for a COPD exacerbation. He has a 60–pack-year history of smoking and quit 20 years ago. Most recent pulmonary function tests demonstrate an FEV₁ (forced expiratory volume in 1 second) of 31% (1.11 L), hyperinflation, decreased diffusing capacity, and a postbronchodilator response of +34%. In the ED, he received steroids and antibiotics, as well as nebulizations with albuterol and ipratropium. He has completed his course of steroids and antibiotics, and he feels well except for an occasional productive cough. His oxygen saturation is 95% on room air, his vital signs are stable, and he is afebrile. His maintenance COPD medications include albuterol MDI (metered-dose inhalers) and nebulizer as needed; ipratropium; and an inhaled corticosteroid. Financial concerns have prevented him from using more or different inhalers up to this point, but his recent ED visit makes him willing to reconsider another inhaler if this will prevent future attacks. You suspect that he might benefit from a long-acting bronchodilator, but you are unsure as to which one will be most effective.

The Question

Which long-acting bronchodilator is most effective for decreasing COPD exacerbations?

Jon O. Ebbert (left) and Eric G. Tangalos

The Search

You open PubMed ( www.pubmed.gov), enter "copd exacerbations AND bronchodilator," and limit to "Randomized Controlled Trial."

The Evidence

"Tiotropium Versus Salmeterol for the Prevention of Exacerbations of COPD" (N. Engl. J. Med. 2011;12:1093-103).

• Study Design and Setting: A 1-year, randomized, double-blind, double-dummy, parallel-group trial with a run-in phase, conducted at 725 centers in 25 countries.

• Participants: Patients were eligible for inclusion in the study if they were at least 40 years old; had a smoking history of 10 pack-years or more, as well as a COPD diagnosis; and had an FEV₁ after bronchodilation of 70% of the predicted value, a ratio of FEV₁ to FVC (forced vital capacity) of 70%, and a documented history of at least one exacerbation leading to treatment with systemic glucocorticoids, antibiotics, or hospitalization within the previous year.

• Intervention: Participants were randomized to receive either tiotropium (18 mcg once daily delivered with the HandiHaler inhalation device) plus placebo (twice daily with an MDI), or salmeterol (50 mcg twice daily with an MDI) plus placebo (once daily delivered with the HandiHaler device). Patients on tiotropium were switched to ipratropium, which was discontinued on randomization; patients on long-acting beta₂-agonists continued therapy through the run-in period; and patients on beta₂-agonists and inhaled steroids were instructed to switch to inhaled steroid monotherapy. Patients were allowed to continue their usual medications for COPD during the double-blind treatment phase, except for anticholinergic drugs and long-acting beta₂-agonists.

• Outcomes: The primary outcome was defined as time to the first exacerbation. An exacerbation was defined as an increase in or new onset of more than one COPD symptom (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting 3 days and leading to the initiation of treatment with systemic steroids, antibiotics, or both, or to hospitalizations. Secondary end points included time to event, number of events, serious adverse events, and death. Data on exacerbations were collected through a questionnaire administered during clinic visits and telephone contacts.

• Results: In all, 7,384 participants were randomized and were similar at baseline. More participants withdrew in the salmeterol group than in the tiotropium group (17.7% vs. 15.8%; P = .02). Time to first COPD exacerbation was increased by 42 days with tiotropium, compared with salmeterol (187 days vs. 145 days; hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). Compared with salmeterol, tiotropium significantly reduced the annual number of moderate or severe exacerbations (0.64 in the tiotropium group and 0.72 in the salmeterol group; 11% reduction; rate ratio (RR), 0.89; 95% CI, 0.83-0.96; P = .002). Effects of tiotropium as compared with salmeterol on the time to a first exacerbation and the annual rate of exacerbations per patient were consistent across prespecified subgroups according to age, sex, smoking status, COPD severity, body mass index, and baseline use of inhaled steroids. No clinically significant differences were observed between groups with respect to adverse events.

Our Critique

This was a large, well-conducted clinical trial that provides useful information for clinicians who are trying to make decisions about the next step in therapy for COPD patients. The large sample size provides the ability to detect smaller differences between the products. Importantly, the benefit of tiotropium, compared with salmeterol, became evident as early as 1 month after treatment initiation, and was independent of steroid use. The cost of these medications remains an important consideration for many patients. This is especially challenging, as many of our patients pay less out of pocket for an ED visit than they do for their monthly medications.

Clinical Decision

You discuss the results with the patient and elect to start tiotropium. You alert him to the fact that the medication costs $230 per month. He is concerned that his insurance will not cover it. You schedule a follow-up visit with him in 3 months to see how he is doing and if he is taking the medication.

Selecting Long-Acting Bronchodilators for COPD