LAUSR

As noted in our paper, we cannot rule out the possibility of some residual confounding by indication [1]. However, the concern of Almagro et al. [2] that confounding by indication could have been a substantive issue appears to be based on a misinterpretation of the data in Table 2. The differences they highlight in relation to the severity of chronic obstructive pulmonary disease (COPD), history of acute coronary syndrome (ACS), five-year risk of a first cardiovascular event, and other characteristics, represent the overall differences in characteristics between cases and controls, not differences between ‘patients treated with LABA+LAMA (long-acting beta2-agonist+long-acting muscarinic antagonist) versus LAMA’/‘patients with dual bronchodilation’ versus those receiving LAMA alone. Moreover, as discussed in our paper, we matched cases and controls by the severity of COPD at the initiation of long-acting bronchodilator therapy so that within each matched case/control set all patients had the same level of COPD severity. The apparent imbalance of COPD severity in the overall comparison of cases and controls in Table 2 is because the number of matched controls per case varied. We took the matching into account in the analyses, undertaking a matched analysis to address the primary aim and adjusting for COPD severity (along with the other matching factors) in the unmatched secondary analyses. In addition, in an earlier national study we examined treatment patterns among patients with mild/moderate COPD severity at cohort entry whose first long-acting bronchodilator therapy was either a LAMA or a LABA [3]. We found that any change in medication after the first increase in COPD severity during follow-up was most often the addition of an inhaled corticosteroid rather than the addition of a second long-acting bronchodilator. This prescribing behaviour, along with the matching of cases and controls on severity of COPD, suggests it is unlikely that the observed association is entirely explained by confounding by indication.