Did the BLOCK-COPD Trial Resolve the Beta-Blocker Controversy?

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Study Authors: Mark T. Dransfield, Helen Voelker, et al.; William MacNee

Target Audience and Goal Statement: Pulmonologists, cardiologists, emergency department physicians, critical care specialists

The goal of this study was to examine if a beta-blocker (extended-release metoprolol) would reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations versus placebo in patients with moderate-to-severe COPD who were prone to exacerbations and who did not have established indications for beta-blocker therapy.

Question Addressed:

• What was the clinical effect of metoprolol versus placebo on the risk of COPD exacerbations among patients who were at high risk for such events?

Study Synopsis and Perspective:

Cooperation between the heart and lungs is vital to good health. The right side of the heart pumps oxygen-poor blood received from the rest of the body into the lungs, where it is oxygenated. Oxygen-rich blood received from the lungs on the left side of the heart is pumped to the rest of the body. Diseases of the lung can co-occur with heart disease. For example, COPD — a disease characterized by chronic airflow limitation and inflammation of the lung — often occurs together with cardiovascular disease (CVD).

Coexistence of both diseases is associated with a worse prognosis than either disease alone. COPD treatments may produce beneficial cardiovascular (CV) effects, but data remain limited as to whether these translate into benefits in CV outcomes. Conversely, beta-blockers are known to save the lives of people with heart disease (specifically post-myocardial infarction and heart failure), but use of this drug class in COPD has been controversial. While non-randomized studies involving patients with COPD have suggested that beta-blockers lower the risk of exacerbations and death (irrespective of the presence of heart disease), others have raised concerns about use of these agents leading to bronchospasm in COPD.

Mark T. Dransfield, MD, of the University of Alabama Birmingham Lung Health Center, and colleagues set out to resolve the controversy over the potential beneficial effects of beta-blockers in COPD. They reported the outcomes from the BLOCK-COPD (Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease) trial at the 2019 CHEST meeting in New Orleans and in the New England Journal of Medicine.

A total of 532 patients with COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 41.1% of the predicted value) were randomized to receive one 50-mg tablet of metoprolol (n=268) or matching placebo (n=264) taken orally daily. The primary outcome was the time to first exacerbation of COPD. Dransfield’s group stopped the trial early because of futility with respect to the primary outcome and safety concerns.

No significant difference was observed in the median time to first exacerbation between the metoprolol and placebo groups (202 days vs 222 days, hazard ratio [HR] 1.05, 95% CI 0.84-1.32, P=0.66). Moreover, metoprolol was linked to a higher risk of exacerbation leading to hospitalization compared with placebo (HR 1.91, 95% CI 1.29-2.83).

There were no significant between-group differences in several other prespecified measures, including the change from baseline in the FEV1, the 6-minute walking distance, and the score on the St. George’s Respiratory Questionnaire. However, when compared with placebo, patients who received metoprolol had greater increases from baseline in scores on the COPD Assessment Test and the San Diego Shortness of Breath Questionnaire. These findings reflect worse COPD control and a worsening in shortness of breath.

Overall, nonfatal serious adverse events occurred at rates of 0.65 and 0.43 per person-year in the metoprolol and placebo groups, respectively. Similarly, nonfatal serious COPD exacerbations occurred at a rate of 0.43 per person-year in the metoprolol group and 0.19 per person-year in the placebo group. Eleven deaths occurred in the metoprolol group and 5 deaths occurred in the placebo group during the treatment period.

Because trial participants had moderate or severe COPD with a high prevalence of supplemental oxygen use and prior hospitalization for the disease, it was not clear whether the results would apply to patients with mild airflow obstruction or a lower exacerbation risk, the researchers acknowledged. Other study limitations included the fact that it was not possible to fully blind researchers and patients to the effects of beta-blocker treatment (e.g., reductions in heart rate and blood pressure) and the inability to identify specific factors predisposing patients to adverse outcomes when treated with metoprolol.

Source References: New England Journal of Medicine 2019; DOI: 10.1056/NEJMoa1908142

Editorial: New England Journal of Medicine 2019; DOI: 10.1056/NEJMe1912664

Study Highlights and Explanation of Findings:

While there was no evidence of a significant difference in the risk of COPD exacerbation between the metoprolol and placebo groups in this prospective, multicenter, randomized trial, the beta-blocker was tied to a higher risk of exacerbation leading to hospitalization. These study findings differed from two published meta-analyses. The first meta-analysis, which included nine studies, showed that patients taking beta-blockers had a lower risk of COPD-related death compared with those not taking beta-blockers (relative risk [RR] 0.69, 95% CI 0.62-0.78). Similarly, the other meta-analysis, which included 15 studies, showed a reduced risk of death from any cause (RR 0.72, 95% CI 0.63-0.83) or from COPD exacerbation (RR 0.63, 95% CI 0.57-0.71). Dransfield attributed the differences between prior observational studies and the current randomized trial to methodological limitations inherent in the design of an observational study. Some of the challenges included the possibilities of residual confounding and immortal time bias, which may have affected prior results.

Although no between-group differences were seen in the 6-minute walk test or in patients’ reports of possible beta-blocker side effects, researchers did observe worsening dyspnea and in the overall burden of COPD symptoms (as measured by the COPD Assessment Test). More people in the metoprolol group discontinued treatment versus the placebo group. Taken together, the results suggested adverse respiratory effects not captured by spirometry.

In an interview with MedPage Today, Dransfield said the findings from the BLOCK-COPD trial confirm that metoprolol is not beneficial, and may be harmful, in patients who do not have indications to be on a beta-blocker.

“If patients with COPD do not have these indications, they should not be on the drug,” he said.

In an editorial published with the study, William MacNee, MD, of the University of Edinburgh Medical School, stressed that clinicians should not be reluctant to prescribe beta-blockers to COPD patients with indications for their use, based on the findings.

He noted that there is little evidence that beta-blockers are currently being prescribed to COPD patients without therapeutic indications for their use.

“On the contrary, there is good evidence that physicians are still reluctant to prescribe beta-blockers even in patients with COPD who have proven cardiac indications,” MacNee wrote. “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 exacerbations.”

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