Inhaled corticosteroids and risk of cardiovascular events in chronic obstructive pulmonary disease: a nationwide cohort study in Denmark

RATIONALE: Cardiovascular disease is a major comorbidity in chronic obstructive pulmonary disease (COPD). Previous studies evaluating the association between inhaled corticosteroids (ICS) and cardiovascular events (CVEs) in COPD have yielded conflicting results and a potential dose-response relationship remains unclear. OBJECTIVES: To determine the association between ICS exposure and risk of CVE in COPD patients. METHODS: In this nationwide, retrospective register-based cohort study, we included patients with a specialist-verified COPD diagnosis between January 2008 and January 2022. ICS exposure was quantified as mean daily budesonide-equivalent dose redeemed in the year prior to index and categorised as none, low (>0 µg/day and <400 µg/day), moderate (400-800 µg/day) or high (>800 µg/day). We assessed CVE risk using adjusted cause-specific Cox proportional hazards models, with additional sensitivity analyses including a complete-case analysis, time-varying Cox regression, Fine-Gray competing risk model, and a negative control outcome analysis. RESULTS: Among 82 327 patients, 8948 (10.9 %) experienced a CVE during a 1-year follow-up. In the primary analysis, low- and moderate-dose ICS was associated with a significantly reduced CVE rate compared with no ICS use. A modest decrease in CVE rate was observed for moderate-dose ICS largely across all sensitivity analyses. CONCLUSION: ICS use in COPD was not associated with an increased risk of CVE at any dose level. A modest association with reduction in CVE risk was confined to moderate-dose ICS. These findings support the cardiovascular safety of ICS and reinforce that ICS prescribing should be guided by exacerbation risk and symptom burden rather than cardiovascular concern.