O7.2.2 Safety of beta-blockers

Beta blockers have well established survival benefits in heart failure and after myocardial infarction and have been long used in coronary artery disease and hypertension but have been considered contra-indicated in patients with COPD. A Cochrane systematic review identified 20 RCTs of cardio-selective beta blockers which examined lung function and respiratory symptoms in 278 patients with COPD (Salpeter 2005, Salpeter 2002) [evidence level I]. Eleven studies were of single dose and nine were of prolonged treatment (mean 3.7 weeks, range two days to 12 weeks).  The beta blockers included atenolol, metoprolol, bisoprolol, practolol, celiprolol and acebutolol and were used at therapeutic doses. There was no significant overall change in FEV₁, respiratory symptoms or the response to inhaled beta₂ agonists.  The authors concluded that cardio-selective beta blockers were safe and should not be withheld, even in patients with severe airflow limitation. However, even with pooled data the absolute patient numbers were small and failed to represent minority groups such as females and the elderly. The longest duration included trial was 12 weeks, and so the meta-analysis provides little guidance about long term safety and potential morbidity of prolonged beta-blocker use in COPD.

Despite a paucity of evidence to suggest harm, beta-blockers are still under-utilised in COPD for guideline-based indications such as systolic heart failure (Lipworth 2016) [evidence level III-2].  Australian data from a COPD cohort hospitalised for a COPD exacerbation also reflects this (Neef 2016) [evidence level III-2] as does a similar New Zealand study (Parkin 2020) [both evidence level III-2]. In contrast, Parkin et al report much higher prescription rates for other medications used to reduce cardiovascular risk, such as aspirin and hydroxymethylglutaryl-CoA reductase inhibitors (statins).

A number of observational studies also lend confidence to beta-blocker prescribing in COPD patients. In Du et al’s meta-analysis (Du 2016) of 15 cohort studies with follow up ranging from one to 7.2 years beta-blocker treatment was associated with reduced mortality (RR 0.72, 95% CI 0.63 to 0.83) and exacerbation risk (RR 0.63, 95% CI 0.57 to 0.71). Despite significant heterogeneity, sensitivity analysis did not change the outcome [evidence level III-2]. Moreover, beta-blocker treatment did not diminish the beneficial effects of inhaled treatments on post bronchodilator FEV₁ or COPD exacerbations (Dransfield 2018).  However, a prospective randomised trial of metoprolol to prevent exacerbations in moderate to severe COPD (Dransfield 2019) reported no benefit (adjusted HR 1.12, 95% CI 0.88 to 1.42), after early termination for futility and potential safety concerns about increased respiratory symptoms and severe exacerbations (adjusted HR 1.91, 95% CI 1.29 to 2.83) in the active treatment group. It is important to note that patients with heart failure and recent intervention for ischaemic heart disease were excluded.  Due to the study’s selection criteria, these results should only apply to patients who have no therapeutic indication for beta-blockers. An RCT of bisoprolol vs placebo over 52 weeks in 515 patients with COPD and frequent exacerbations reached only 33% of target recruitment (due to the COVID-19 pandemic) and showed no statistically significant difference in rates of COPD exacerbations (rate ratio 0.97, 95% CI 0.84 to 1.13) (Devereaux 2024) [evidence level II]. Prospective data for COPD patients with cardiac disease are still needed.