Beta-blockers in patients with heart failure with reduced ejection fraction and concomitant chronic obstructive pulmonary disease: cardiovascular and respiratory outcomes

We thank Chai and Wang for their thoughtful comments on our recent analysis of beta-blockers in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant chronic obstructive pulmonary disease (COPD).1 First, to identify severe COPD exacerbations, we adopted a broad definition including respiratory hospitalizations rather than restricting events to COPD-specific diagnosis codes. This approach is commonly adopted in COPD registry research, where misclassification of COPD as the primary diagnosis is common, and differentiation between pneumonia and COPD exacerbation is often challenging even in adjudicated datasets.2,3 Although this definition might include events not directly caused by COPD per se, it was chosen to better capture the overall respiratory safety profile, as hospitalization for respiratory causes in patients with established COPD is likely to reflect COPD-related morbidity. Second, we agree that outpatient-treated exacerbations are of clinical interest. However, our safety hypothesis was primarily informed by the BLOCK COPD trial, which reported an excess of severe exacerbations (i.e. hospitalizations) but not of moderate (i.e. outpatient) exacerbations in metoprolol vs placebo.4 Accordingly, our analysis focused on hospitalized events as the outcome most aligned with the safety concerns that arose from BLOCK COPD. Recently, the randomized trial PACE, enrolling a broader COPD population, showed no increase in severe or moderate exacerbations with bisoprolol.5