1. In this double-blind randomized trial of COPD patients without previous indication for beta blocker therapy, treatment with extended-release beta-blockers failed to generate improved health outcomes versus placebo. No significant between-group difference was found in the median time until the first exacerbation of COPD.
2. Patients in the metoprolol group were more likely to experience severe exacerbations and to discontinue treatment compared to patients given placebo. A nonsignificant doubling of mortality was also observed in the metoprolol group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: In patients with chronic obstructive pulmonary disease (COPD), underlying cardiovascular disease is a common major risk factor for exacerbations that can lead to hospitalization and reduced survival. Beta-blockers are a mainstay of treatment for patients with heart failure, but the use of these therapeutic agents is often contraindicated in COPD patients due to potentially severe adverse effects on lung function. While multiple observational studies have suggested that beta-blockers may be an effective treatment option for patients with COPD, a causal relationship has not yet been established due to possible biases inherent in the study methodology. This prospective randomized trial aimed to determine the effect of beta-blockers on the risk of exacerbations and death in patients with moderate to severe COPD without established indication for beta blocker therapy. Findings showed no significant between-group difference in the median time until the first exacerbation although those in the beta-blocker group were more likely to be hospitalized for exacerbations. Worsening of lung function assessed through spirometry was not observed in this study or in meta-analysis, but administration of beta-blockers was linked to an increased overall burden of COPD symptoms and resulted in more discontinuations versus placebo, suggesting that adverse effects were still present. These findings cast doubt on the efficacy of beta-blockers in treating COPD, highlighting the need for further research into this area.
This study boasted a large sample size and a randomized, double-blind design. However, the physiological effects of beta-blockers (lowered heart rate and blood pressure) were difficult to mask and therefore may have introduced bias. In addition, conclusions were difficult to generalize because of the homogeneity and specificity of the trial population as well as the cardioselective nature of the tested beta-blocker, metoprolol.
In-Depth [randomized control trial]: This multicenter, placebo-controlled, double-blind, prospective, randomized trial recruited 532 COPD patients between 2016 and 2019 with moderate airflow limitation as defined by the Global Initiative for Obstructive Lung Disease and an increased risk of exacerbations.Other inclusion criteria were a normal resting heart rate and resting systolic blood pressure >100 mmHg. Patients who had a proven indication for the use of a beta-blocker were excluded from the study. The primary end point was the median time until the first exacerbation (defined as an increase in two or more of the following: cough, sputum production, wheezing, dyspnea, or chest tightness requiring treatment with antibiotics or glucocorticoids). Secondary end points included rate of exacerbations, all-cause hospitalization and mortality, and measures of quality of life. No significant between-group difference was found in median time until first exacerbation (adjusted hazard ratio, 1.12; 95% CI, 0.88 to 1.42), but on average, the metoprolol group experienced a significantly shorter median time until first moderate exacerbation (adjusted hazard ratio, 1.46; 95% CI, 1.03 to 2.06) and severe exacerbation (adjusted hazard ratio, 2.08; 95% CI, 1.37 to 3.14). No between-group difference was detected in the overall rates of exacerbation, but the metoprolol group faced a higher rate of severe exacerbation (rate ratio, 1.51; 95% CI, 1.00 to 2.29) and very severe exacerbation (rate ratio, 3.71; 95% CI, 1.10 to 16.98). Mortality also varied between groups during the treatment period with 11 in the metoprolol group and 5 in the placebo group (adjusted hazard ratio, 2.13; 95% CI, 0.69 to 6.42).
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