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

Int J Chron Obstruct Pulmon Dis. 2022 May 20:17:1205-1217. doi: 10.2147/COPD.S358927. eCollection 2022.


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.

MeSH terms

  • Administration, Inhalation
  • Adrenergic beta-2 Receptor Agonists / adverse effects
  • Asthma* / diagnosis
  • Asthma* / drug therapy
  • Bronchodilator Agents / adverse effects
  • Cardiovascular Diseases* / chemically induced
  • Cardiovascular Diseases* / diagnosis
  • Cardiovascular Diseases* / epidemiology
  • Case-Control Studies
  • Humans
  • Pulmonary Disease, Chronic Obstructive* / complications
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy


  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents

Grants and 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.