Beta-Blockers Hit With Another Negative Trial in COPD

Once again, a beta-blocker failed to prove beneficial in people with chronic obstructive pulmonary disease (COPD) without cardiovascular disease in a randomized trial.

In BRONCHIOLE, people randomized to metoprolol plus standard care had no fewer primary endpoint events during 1 year of follow-up (27.4% vs 29.9% with standard care alone, HR 0.87, 95% CI 0.73-1.05), according to Josefin Sundh, MD, PhD, of Örebro University in Sweden, reporting at the European Respiratory Society (ERS) Congress, held this year in Barcelona, Spain.

However, individual components of the primary composite endpoint consistently leaned in favor of the metoprolol group without reaching statistical significance:

• COPD exacerbations: HR 0.88 (95% CI 0.72-1.06)
• Cardiovascular events: HR 0.73 (95% CI 0.48-1.11)
• Death: HR 0.92 (95% CI 0.48-1.77)
• Exacerbations requiring hospitalization: HR 0.87 (95% CI 0.58-1.28)

In the metoprolol and control groups, serious adverse events occurred in 9.4% and 7.8%, respectively, and nonserious adverse events in 34.6% and 29.2%. The most commonly reported symptoms with metoprolol were fatigue (21.7%), symptoms attributed to low blood pressure (15.9%), and gastrointestinal symptoms (7.9%).

The study was published simultaneously in NEJM Evidence.

“These findings are consistent with previous randomized trials of beta-blocker therapy in COPD, which were limited by early termination or insufficient power. The current trial extends the evidence base by providing data from a larger pragmatic trial that included participants across all GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages, thereby improving generalizability,” study authors wrote.

“A previous meta-analysis supported the safety of beta-blockers in patients with COPD and established cardiovascular disease. The current findings extend this evidence to a broader COPD population, including patients with cardiovascular risk factors such as hypertension and tachycardia but without established cardiovascular disease,” they added.

Sundh’s group explained that cardioselective beta-blockers have been shown to improve survival in patients with COPD who have ischemic heart disease or heart failure. They are believed to also have benefit in COPD alone — absent cardiovascular disease — though trial after trial has failed to prove it.

“BRONCHIOLE now represents the fourth negative trial for beta-blockers in COPD, and the readiest conclusion may be that these medications are not beneficial for any cardiorespiratory outcome,” commented R. Chad Wade, MD, and Mark T. Dransfield, MD, both of the University of Alabama at Birmingham and the Birmingham VA Healthcare System.

“However, a tempered response may be warranted,” they wrote in an accompanying editorial. “While certain populations may be at higher risk for harm with beta-blockers, BRONCHIOLE and the other bisoprolol trials provide reassuring evidence of safety in COPD.”

Future beta-blocker studies should focus on “comprehensive phenotyping and adequate sample size to identify potential responders and exclude groups at higher risk of harm,” the editorialists suggested. “Until then, BRONCHIOLE offers reassurance that beta-blockers should not be withheld in patients with COPD with guideline-indicated conditions for their use.”

The trial was conducted at 30 sites in Sweden as an open-label, pragmatic trial. Enrolled were patients aged 40 years or older with COPD, sinus rhythm, and no cardiovascular disease.

Investigators had 1,695 people (mean age 70 years, 62% women) randomized to receive metoprolol in addition to standard care or standard care alone.

Of those assigned metoprolol, 49.4% reached the target dose of 100 mg once daily, 30.8% continued with 50 mg once daily, and 19.8% discontinued metoprolol during follow-up.

Of note, there appeared to be some interaction by sex regarding results of the primary composite endpoint: Metoprolol was associated with significant benefit in women (HR 0.70, 95% CI 0.56-0.88) but not among men (HR 1.28, 95% CI 0.94-1.74).

“However, this trial was not designed to determine the mechanisms underlying the sex-specific difference in treatment effect. This finding should therefore be considered hypothesis-generating and warrants further study,” Sundh and colleagues cautioned.

BRONCHIOLE was further limited by its lack of blinding of investigators or patients and a lower-than-expected event rate.