Metoprolol leads to early declines in lung function among patients with COPD

Patients with COPD experienced early, but modest and nonpersistent, reductions in lung function during treatment with metoprolol, according to a post-hoc analysis of the BLOCK COPD study in The Annals of the American Thoracic Society.

Further, baseline FVC bronchodilator response predicted severe/very severe exacerbations in adjusted analysis but, otherwise, researchers found no difference between declines in early lung function or baseline bronchodilator responsiveness and the risk for exacerbations when comparing metoprolol with placebo.

As Healio previously reported, the BLOCK COPD study showed an increased risk for severe exacerbation among patients treated with metoprolol, a beta-blocker, than patients treated with placebo, leading the study to be closed early for futility.

“There is no definitive explanation for the higher risk of severe exacerbation seen in the metoprolol group [of the BLOCK COPD trial]; however, there have been long-standing concerns about the potential adverse respiratory effects of beta-blockers,” Trisha M. Parekh, DO, assistant professor in the division of pulmonary, allergy and critical care medicine at The University of Alabama at Birmingham, and colleagues wrote.

To better determine why metoprolol failed to prevent COPD exacerbations, Parekh and colleagues evaluated 532 patients with COPD aged 40 to 85 years who received metoprolol (n =268) or placebo (n = 264) over 336 days in the BLOCK COPD study to observe changes in lung function.

Researchers used linear mixed-effect models to compare changes in lung function (FEV₁ or FVC) between treatment groups, and they used Cox proportional hazards models to evaluate the relationship between bronchodilator response (FEV₁, FVC or combined), early lung function reduction at day 14 and risk for exacerbations based on treatment group.

Researchers measured changes in FEV₁ and FVC at visits taken from baseline to day 14, 28, 42, 112 and 336.

Change in absolute FEV₁ did not differ by treatment over the study period, but researchers observed a significantly greater decrease in logarithmic FEV₁ in the metoprolol group than in the placebo group from baseline to day 28, at 0.039 (95% CI, –0.069 to –0.009).

Compared with patients treated with placebo, patients treated with metoprolol also had significant absolute FVC declines of 67.2 (95% CI, –128.7 to –5.8) from baseline to day 14 and 79.2 (95% CI, –141.1 to –17.3) from baseline to day 28. Logarithmic FVC also significantly decreased in this group by 0.032 (95% CI, –0.061 to –0.003) from baseline to day 42 and by 0.031 (95% CI, –0.061 to 0) from baseline to day 112, according to researchers.

When considering changes in lung function up until day 14, researchers did not find a relationship between the type of treatment and time to any or severe/very severe exacerbation.

Additionally, bronchodilator responsiveness measures did not predict time to, risk for or rate of any severe/very severe exacerbation between the groups.

However, researchers found that patients who had baseline FVC bronchodilator responsiveness had a 1.58 (95% CI, 1.01-2.45) higher unadjusted rate and a 1.62 (95% CI, 1.04-2.48) higher adjusted rate of severe/very severe exacerbations.

“Our study did not find an explanation for a higher risk of severe exacerbations in the metoprolol group seen in the BLOCK COPD trial,” Parekh and colleagues wrote. “Although there were some changes in FEV₁ and FVC in the metoprolol group early in the study, neither early lung function decline nor [bronchodilator responsiveness] interacted with treatment assignment in predicting either time to or rate of exacerbation.

“Our results suggest that FVC [bronchodilator responsiveness] may impact the rate of exacerbations, independent of metoprolol use, and may have a role in determining clinical phenotypes,” Parekh and colleagues added.

In an accompanying editorial, Robert J. Hancox, MD, research professor and head of the department of preventive and social medicine at the University of Otago in New Zealand, highlighted the challenges physicians face in treating patients with COPD and cardiac indications for beta-blocker treatment, because the BLOCK COPD trial and post-hoc analysis by Parekh and colleagues did not evaluate this subgroup.

“Until we have more data, clinicians will need to balance the likely cardiac benefits from cardioselective beta-blocker treatment with the observed increased risk of a severe COPD exacerbation,” Hancox wrote. “The article by Parekh and colleagues shows that monitoring the lung function response to beta-blockers is unlikely to help. Patients should be informed of the risks and involved in the decision. If it is decided to start a beta-blocker, it seems sensible to use the most cardioselective beta-blocker available.”

Reference:

Hancox RJ. Ann Am Thorac Soc. 2022;doi:10.1513/AnnalsATS.202207-609ED.