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Beta-blocker fails to prevent COPD exacerbations

NEW ORLEANS — In patients with moderate to severe COPD without an established indication for beta-blocker use, treatment with metoprolol did not reduce the risk for exacerbations compared with treatment with placebo, results from the BLOCK COPD trial suggest.

Observational studies have suggested that beta-blockers reduce risk for COPD exacerbations and death, even in the absence of cardiovascular disease, according to Mark Dransfield, MD, from the Lung Health Center at the University of Alabama at Birmingham.

“In this trial, we hypothesized that metoprolol would lower the risk for exacerbation in COPD patients at risk for those events without having an adverse effect on lung function, 6-minute walk distance, dyspnea or quality of life,” Dransfield said at the CHEST Annual Meeting.

However, in the multicenter, double-blind, randomized, controlled study, Dransfield and colleagues found no significant difference in the primary endpoint — median time to first COPD exacerbation — when comparing patients in the metoprolol group with those in the placebo group (202 vs. 222 days; HR = 1.05; 95% CI, 0.84-1.32; P = .66). Moreover, the risk for exacerbation leading to hospitalization or exacerbation requiring mechanical ventilation was significantly higher among patients receiving metoprolol than among those receiving placebo (HR = 1.91; 95% CI, 1.29-2.83).

Subsequently, the study, which was simultaneously published in The New England Journal of Medicine, was terminated early due to a lack of benefit accompanied by a potential safety signal among patients in the metoprolol group.

No difference in secondary endpoints

In other findings, there were no significant differences between the metoprolol and placebo groups in the overall rate of any exacerbations and changes from baseline in FEV₁, 6-minute walk distance and St. George’s Respiratory Questionnaire scores. However, patients receiving metoprolol had greater increases from baseline in COPD Assessment Test and San Diego Shortness of Breath Questionnaire scores, indicating worse COPD control and worsening dyspnea.

The overall rate of nonfatal and fatal serious adverse events was numerically higher in the metoprolol group than in the placebo group (0.65 vs. 0.43 per person-year; P = .07) — a difference that was primarily driven by COPD exacerbations (0.43 vs. 0.19 per person-year; P = .02). It is important to note, though, that these exacerbation events were investigator-reported as opposed to protocol-defined and therefore may or may not meet the criteria that was used to determine an exacerbation based on the primary endpoint, Dransfield noted.

Overall, 11 deaths occurred in the metoprolol group and five occurred in the placebo group during the treatment period — a difference that did not reach statistical significance (P = 0.14).

Interestingly, there were also no differences between groups in the frequency of patient-reported adverse events that were potentially related to metoprolol, although more patients in the metoprolol group discontinued medication than in the placebo group (11.2% vs. 6.1%), most commonly due to respiratory symptoms, according to Dransfield.

Interpretations

The BLOCK COPD enrolled 532 patients aged 40 to 85 years with COPD (mean age, 65 years; mean FEV₁, 41.1% predicted) from May 2016 to the study’s termination in March 2019. All patients had moderate airflow limitation, had increased risk for exacerbations, were current or former smokers and did not have a class I indication for beta-blocker use. Patients were randomly assigned one 50-mg tablet of metoprolol or matching placebo, with dose adjustment occurring over the next 42 days. The researchers followed patients for 336 days.

In light of the findings, there is currently no role for metoprolol in reducing the risk for exacerbations in patients with COPD without a class I indication for beta-blockers, Dransfield noted.

“The other important conclusion is although observational studies suggest that the benefits of beta-blockers in patients with myocardial infarction and heart failure extend to patients with COPD, that has not actually been prospectively validated and randomized trials may be needed,” he said.

In an accompanying editorial, William MacNee, MB, ChB, MD, from the University of Edinburgh School of Medicine, put the BLOCK COPD findings in perspective. Specifically, he highlighted the fact that observational studies typically include patients with overt CVD who therefore did not require beta-blocker treatment. He also noted that the BLOCK COPD patient population had severe COPD and were at high risk for exacerbations. Consequently, the study results are applicable to those types of patients.

“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,” MacNee wrote. – by Melissa Foster

References:

Dransfield MT. New England Journal of Medicine Featured Trial: Beta Blockers for the Prevention of Acute Exacerbations of COPD. Presented at: CHEST Annual Meeting; Oct. 19-23, 2019; New Orleans.

Dransfield MT, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908142.

MacNee W. N Engl J Med. 2019;doi:10.1056/NEJMe1912664.

Disclosures: The study was funded by the U.S. Department of Defense. Dransfield reports he has received personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mereo, PneumRx/BTG and Quark Pharmaceuticals; grants from the American Lung Association, the Department of Veterans Affairs and the NIH; other financial relationships with AstraZeneca, Boehringer Ingelheim, Boston Scientific, GlaxoSmithKline, Novartis, PneumRx/BTG, Pulmonx and Yungjin; and non-financial support from Pulmonx. MacNee reports he has received personal fees from AstraZeneca and GlaxoSmithKline and grants and personal fees from Pfizer.