Association between Inhaled β₂-agonists Initiation and Risk of Major Adverse Cardiovascular Events: A Population-based Nested Case-Control Study

Abstract

Purpose

Despite ample evidence underpinning the efficacy of β₂-agonists in asthma and chronic obstructive pulmonary disease (COPD), the occurrence of β₁- and β₂-adrenoceptors in the heart suggests that β₂-agonists may have deleterious cardiac effects. We investigated the association between new users of long-or short-acting β₂-agonists (LABA or SABA) or ICS (inhaled corticosteroids)/LABA and major adverse cardiovascular events (MACE).

Methods

A nested case–control analysis was conducted using the UK Clinical Practice Research Datalink of patients with asthma, COPD or asthma–COPD overlap with initial treatment of LABA, SABA, ICS/LABA, ICS, long-or short-acting muscarinic antagonist (LAMA or SAMA) between 01 January 1998 and 31 July 2018. The primary outcome was MACE, defined as the first occurrence of stroke, heart failure, myocardial infarction, arrhythmia, or cardiovascular death. Each case was matched with up to 10 controls on age, sex, date of cohort-entry, and duration of follow-up. The risk of MACE associated with β₂-agonists was estimated using conditional logistic regression after controlling for potential confounders.

Results

The cohort included 180,567 new users of β₂-agonists, ICS, SAMA, or LAMA. Among asthmatics, β₂-agonists were not associated with the risk of MACE (SABA vs ICS: HR 1.29 [0.96–1.73]; ICS/LABA vs ICS, HR 0.75 [0.33–1.73]). In contrast, among COPD patients, LABA (HR, 2.38 [1.04–5.47]), SABA (HR, 2.02 [1.13–3.59]) and ICS/LABA (HR, 2.08 [1.04–4.16]) users had an increased risk of MACE compared with SAMA users. Among patients with asthma–COPD overlap, SABA (HR, 2.57 [1.26–5.24]) was associated with an increased risk of MACE compared with ICS.

Conclusion

In conclusion, initiation of LABA, SABA, or ICS/LABA in COPD or SABA in asthma–COPD overlap is associated with increased risk of MACE. No associations were observed among patients with asthma.

Keywords:

• asthma
• chronic obstructive pulmonary disease
• nested case–control

Abbreviation

COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Datalink; ICS, inhaled corticosteroid; SAMA, short-acting muscarinic antagonist; LABA, long-acting β₂-agonists; LAMA, long-acting muscarinic antagonist; MACE, major adverse cardiovascular events; SABA, short-acting β₂-agonists; HR, hazard ratio.

Acknowledgments

This study is based on data from the Clinical Practice Research Datalink (CPRD-GOLD) obtained under license from the UK Medicines and Healthcare products Regulatory Agency. However, the interpretation and conclusions contained in this study are those of the authors alone.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by a research grant from Canada Research Respiratory Network (CRRN), Ottawa, Canada (Young Investigator Award, 2017). The study funder was not involved in the study design or the writing of the protocol.