Metoprolol for the Prevention of Acute Exacerbations of COPD

Abstract

Background: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.

Methods: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.

Results: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV₁) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.

Conclusions: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Figure 1.. Screening, Randomization, and Follow-up.

Among the 145 patients who were excluded from the trial, several had more than one reason for exclusion. Patients were excluded from the trial if they had a class I indication for receipt of a beta-blocker (a history of myocardial infarction or revascularization within the previous 36 months or heart failure with a known left ventricular ejection fraction of less than 40%), according to the guidelines of the American College of Cardiology and the American Heart Association. ECG denotes electrocardiography, FEV₁ forced expiratory volume in 1 second, and FVC forced vital capacity.

Figure 2.. Exacerbations of Chronic Obstructive Pulmonary Disease (COPD).

Panel A shows the Kaplan-Meier estimate of freedom from exacerbation of COPD in the two trial groups. The median time until the first exacerbation was 202 days in the metoprolol group and 222 days in the placebo group. Panel B shows the probability of freedom from either a severe exacerbation (leading to hospitalization) or a very severe exacerbation (leading to hospitalization with intubation and mechanical ventilation). Severe or very severe exacerbations occurred in 26.1% of the patients in the metoprolol group and in 14.8% of those in the placebo group.