Beta-Blocker Fails to Prevent COPD Exacerbations (2024)

— However, trial results don't affirm safety risks suggested by other studies

by Elizabeth Short , Staff Writer, MedPage Today May 20, 2024

SAN DIEGO -- The beta-blocker bisoprolol did not improve exacerbations in chronic obstructive pulmonary disease (COPD) patients, a randomized clinical trial found.

Exacerbations requiring antibiotics, oral corticosteroids, or both occurred at a similar rate of 2.03 per year among COPD patients treated with bisoprolol and 2.01 per year among placebo-treated controls (adjusted incidence rate ratio 0.97, 95% CI 0.84-1.13, P=0.72), reported Brian Lipworth, MD, of the University of Dundee in Scotland, at the American Thoracic Society annual meeting.

Bisoprolol was associated with reduced COPD-related mortality (HR 0.19, 95% CI 0.04-0.88) but not all-cause mortality (HR 0.77, 95% CI 0.34-1.73), according to results of the double-blind trial, which were simultaneously published in JAMA.

"Although there was a difference in COPD-related mortality, what I want you to note there is that the numbers were small," said Lipworth. "Personally, I wouldn't really read too much into that impact on COPD mortality."

At the same time, he added, "we didn't see any safety concerns or serious adverse events either."

The results come against a mixed set of findings from prior studies: A meta-analysis suggested reduced mortality risk and exacerbations with this drug class, while a cohort study and a time-dependent analysis found an increase in mortality risk with treatment.

Meanwhile, the randomized BLOCK COPD study of long-acting beta-blocker metoprolol as a treatment for COPD exacerbations among a more ill population was terminated early due to both safety concerns and futility in preventing COPD exacerbations. Metoprolol actually led to more frequent exacerbations and an increase in breathlessness from baseline.

MeiLan K. Han, MD, of the University of Michigan in Ann Arbor, and Mark T. Dransfield, MD, of the University of Alabama in Birmingham, noted that while the safety findings from Lipworth's group seem promising, BLOCK COPD casts a shadow over the use of beta-blockers for COPD.

"Ultimately, the decision to use beta-blockers for any given patient with COPD without coexisting cardiovascular disease still requires careful consideration based on the data to date," the pair wrote in an editorial accompanying the JAMA paper. "A personalized approach considering individual risk factors and potential benefits is essential when treatment decisions for these patients are made."

The editorialists also expressed concern regarding the sample size of the current study, stating that it is important to "consider whether either a positive primary outcome or a signal for harm could have been missed."

The current trial, BICS (Bisoprolol in COPD Study), was conducted at 45 primary care clinics and 31 secondary care clinics in the U.K. Patients ages 40 and older (average 68) with at least moderate airflow obstruction COPD were randomized 1:1 to receive either bisoprolol or placebo tablets.

Doses of bisoprolol began at 1.25 mg once daily and were up-titrated over the course of about 7 weeks to up to 5 mg daily for the rest of the 52-week trial period.

Eligibility requirements for the study also included a smoking history of 10 pack-years or more and at least two exacerbations requiring treatment with oral corticosteroids, antibiotics, or both within the prior year (average 3.5). Exclusion criteria included asthma diagnosed before age 40, a resting heart rate under 60 bpm, and a systolic blood pressure below 100 mm Hg.

The primary analysis included 514 patients. Nearly half of the study population was female, the average BMI was around 27, and approximately 30-32% were current smokers, with an average history of about 45 pack-years.

There was a borderline significant difference in the Transition Dyspnea Index score–quantified dyspnea suggesting worse breathlessness at 52 weeks with bisoprolol (-0.73 on a scale where 1 point is the minimum clinically important difference, P=0.05).

As a secondary endpoint, median time to first COPD exacerbation following randomization was similar for bisoprolol and placebo (aHR 0.94, 95% CI 0.78-1.16, P=0.60). No significant differences emerged between groups either for COPD exacerbations or non-COPD-related hospitalizations.

Further analysis revealed that there was no evidence suggesting that treatment differed based on age, sex, smoking status, BMI, baseline COPD treatments, exacerbation history, Global Initiative for Chronic Obstructive Lung Disease COPD classifications, bisoprolol dose, or use of maintenance oral corticosteroids (all interaction P>0.05).

Serious adverse event rates were similar between groups, and bisoprolol was not associated with more respiratory serious adverse events (9.8% on bisoprolol vs 12.3% with placebo).

Trial recruitment had been suspended for 16 weeks due to the COVID-19 pandemic, which led to notably lower enrollment numbers than original targets.

Other limitations were that 18% of bisoprolol patients could not withstand titration of the drug and that 31% of study patients took below 70% of expected doses, although adherence was similar between treatment groups. Researchers also cited somewhat high discontinuation levels, missing racial and ethnicity data, and potential unblinding in the treatment group as limitations.