Beta-agonist Inhalers More than Double Death Risk in COPD

STANFORD, Calif., July 10 -- Patients with chronic obstructive pulmonary disease (COPD) who used inhaled beta-2 agonists had more than twice the risk for respiratory death than those who used anticholinergic agents, according to investigators here.

Although they are widely prescribed for COPD, beta-agonist inhalers more than doubled the risk of death in patients with the disease, said Shelley R. Salpeter, M.D., of Stanford and colleagues at Cornell University in Ithaca, N.Y.

In contrast, anticholinergic inhalers such as Spiriva (tiotropium) and Atrovent (ipratropium) reduced the risk of severe exacerbations by 33%, and cut the risk of death by 73%, the investigators reported in the early online version of the Journal of General Internal Medicine.

Yet anticholinergics account for only about 5% of all prescriptions for COPD, the investigators noted.

"When patients used the anticholinergics, they experienced fewer severe exacerbations requiring hospitalizations and fewer respiratory deaths than those taking only a placebo," said Edwin Salpeter, Ph.D., an astrophysicist at Cornell, who also analyzes medical statistics. "With the beta-agonists, it's the other way around, where the number of respiratory deaths increased when compared with those who took only the placebo."

The authors conducted a meta-analysis of pooled results from 22 trials with 15,276 participants. They included only randomized trials lasting at least three months in which anticholinergics and beta-2 agonists were compared with placebo or with each other in patients with COPD.

The anticholinergic agents included in the analyses were Atrovent and Spiriva. The beta-2 agonists studied included Alupent (metaproterenol), Foradil (formoterol), Serevent (salmeterol) Advair (salmeterol and fluticasone), and various brands of albuterol, such as Proventil, Ventolin, and Volmax.

They looked at the relative risk for exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, or deaths attributed to a lower respiratory event.

They found that the use of anticholinergic inhalers significantly reduced the incidence of severe exacerbations compared with placebo, with a relative risk of 0.67 (95% confidence interval 0.53 to 0.86). Anticholinergic agents also reduced the risk of respiratory deaths by 73% (relative risk 0.27, 95% CI 0.09 to 0.81).

In contrast, beta-2 agonists did not have an effect on severe exacerbations (relative risk 1.08, 95% CI, 0.61 to 1.95), and they were associated with a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo.

In addition, when the beta-2 agents were compared with anticholinergics, the beta-2 agonists were associated with a nearly two-fold risk for severe exacerbations (RR 1.95, 95% CI, 1.39 to 2.93).

The addition of beta 2-agonists to anticholinergics did not improve any clinical outcomes, the authors noted.

Although beta-2 agonists are effective bronchodilators, previous studies have shown that patients with COPD can develop tolerance to the effects of beta-2 agonists over time, so that there may be a significant decline in treatment effect at three months compared with the first dose.

In addition, patients with COPD have also been shown to have increased bronchial hyperresponsiveness with regular use of beta-2 agonist inhalers.

"Both anticholinergics and beta-2 agonists may be effective bronchodilators and improve symptoms in patients with COPD," the authors noted. "However, beta-2 agonists had no effect on severe exacerbations and resulted in an increased rate of respiratory deaths, possibly owing to a reduction in disease control. Concomitant corticosteroids were used in over one-half of patients treated with beta-2-agonists, but it is not clear if this provided some protection against the adverse effects."

They also pointed out that, "it is unfortunate that no true placebo-controlled trials of beta-2-agonist use in COPD have been published."

"The results of this meta-analysis suggest that anticholinergics should be the bronchodilator of choice in patients with COPD. The long-term safety of beta-2 agonists in patients with COPD should be addressed," they concluded.