Higher Hospitalization Risk

Results indicated 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 found, however, to be associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83).

With 11 deaths in the metoprolol group and five in the placebo group, the study said that the side effect frequency that could be related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events.

Despite long-stated concerns, researchers emphasize that they did not find evidence of a difference in the risk of COPD exacerbation between the metoprolol group and the placebo group, although hospitalization appeared to be more likely after exacerbation in those using metoprolol.

In addition, they write, “These results differ from previously reported findings from observational studies suggesting that beta blockers reduce the risks of exacerbation and death from any cause in patients with COPD. Although observational studies have suggested that the benefits of beta blockers in patients with recent myocardial infarction and heart failure extend to those with COPD, this hypothesis has not been prospectively confirmed, and randomized trials to determine the overall risk-benefit ratio in such patients may be needed.”

The question raised by an accompanying commentary is whether the study resolves the controversy about use of beta blockers in COPD patients.²

“The trial was stopped early because of the futility of achieving a salutary outcome for the primary endpoint,” notes commentator William MacNee, MB, ChB, MD, of the University of Edinburgh Medical School in Scotland.

“This finding, accompanied by a potential safety signal with respect to exacerbations, sealed the trial’s fate,” MacNee notes. “There was no between-group difference in the time until the first exacerbation or in the overall rate of exacerbation. However, among the patients who received metoprolol, there was a greater risk of severe exacerbation (leading to hospitalization) and very severe exacerbation (leading to intubation and mechanical ventilation). Although the FEV₁ was similar in the two groups, there was a greater increase in a score for breathlessness in the metoprolol group, which suggests an adverse effect of the drug on COPD symptoms. There were more deaths in the metoprolol group, although this result should be treated with caution because of the wide confidence interval around the point estimate.”

He explains that the population in the trial was different from the patients in the observational studies in that it did not have overt cardiovascular disease and, therefore, did not have an indication for treatment with a beta blocker—which differed from patients in the observational studies.

They also were also at high risk for exacerbation and had at least one exacerbation during the preceding year, and more than 50% had visited an emergency department or been admitted to a hospital during the preceding year, MacNee points out.

“Thus, the results of this trial are applicable to patients who do not have a therapeutic indication for treatment with a beta blocker and who have severe COPD with a high risk of severe exacerbations,” he notes. “The trial does not provide any support for the use of beta blockers in such patients for the prevention of an exacerbation of COPD. There is little evidence that beta blockers are currently prescribed for this indication.”

He adds, however, that good evidence exists about the hesitancy of physicians to prescribe beta blockers, even in patients with COPD who have proven cardiac indications. “The results of this trial should not deter the use of beta blockers in patients with COPD who have cardiovascular indications, with the caveat that the risk-benefit ratio should be considered carefully in patients with very severe COPD at high risk for severe exacerbation,” he concludes.

1.    Dransfield MT, Voelker H, Bhatt SP, Brenner K, et. Al.;BLOCK COPD Trial Group. Metoprolol for the Prevention of Acute Exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142. [Epub ahead of print] PubMed PMID: 31633896.

2. MacNee W. Beta-Blockers in COPD – A Controversy Resolved? N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMe1912664. [Epub ahead of print] PubMed PMID: 31633892.