Chronic obstructive pulmonary disease (COPD) is a serious, progressive disease with a high readmission rate for exacerbations and with 3 to 4 percent in-hospital mortality. The mainstays of treatment are inhaled corticosteroids and bronchodilators. Beta₂ agonists are effective for symptom relief, but long-term use is associated with tolerance. Recent reports of greater morbidity and mortality associated with beta₂ agonists have increased concern about their use. Anticholinergics are as effective as bronchodilators and are not systemically absorbed. Even though they may be safer, they are not prescribed nearly as often as beta₂ agonists. Salpeter and colleagues compared the safety profiles of these two classes of bronchodilators.

The authors conducted a review of randomized controlled trials of at least three months’ duration in which anticholinergics or beta₂ agonists were compared with placebo or each other. The 22 eligible trials represented 15,276 participants or 25,460 patient-years.

Drop-out rates and concomitant corticosteroids were similar overall in studies of anticholinergic and beta₂-agonist use. Anticholinergics reduced the risk of moderate COPD exacerbation (i.e., requiring withdrawal from the study) by 40 percent and severe exacerbation (i.e., requiring hospitalization) by 33 percent (number needed to treat [NNT] = 25). Death from respiratory causes was reduced by 73 percent (NNT = 278).

The beta₂-agonist trials were constructed so that they were, in effect, comparing regular long-acting beta₂ agonists with as-needed, short-acting use. Moderate exacerbations were reduced by 19 percent, but severe exacerbations were not reduced. Risk of death increased, with a relative risk (RR) of 2.47. Of note, 60 percent of the deaths contributing to these data came from a single unpublished trial.

Head-to-head comparisons of anticholinergics versus beta₂ agonists showed more moderate (RR = 2.02) and severe (RR = 1.95) exacerbations with the beta₂ agonists, as well as a nonsignificant trend toward greater mortality. There also was no advantage to combining these two medications compared with using anticholinergics alone.

This meta-analysis showed a 0.36 percent absolute risk reduction for respiratory deaths with anticholinergics and a risk increase of 0.76 percent with beta₂ agonists. Although beta2 agonists decrease less severe exacerbations of COPD and improve symptoms, they tend to result in tolerance to bronchodilator and bronchoprotective effects.

The authors conclude that anticholinergics are superior to beta₂ agonists in reducing severe exacerbations and respiratory deaths. Anticholinergics account for only 5 percent of prescriptions for COPD in the United States. Important limitations of this study include the small number of deaths in this pooled analysis. In addition, the study could not draw any conclusions about concomitant effects of inhaled corticosteroids.