Risk Assessment of Acute Myocardial Infarction and Stroke Associated with Long-Acting Muscarinic Antagonists, Alone or in Combination, versus Long-Acting beta2-Agonists

Int J Chron Obstruct Pulmon Dis. 2022 Aug 2:17:1715-1733. doi: 10.2147/COPD.S363997. eCollection 2022.

Abstract

Background: The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists.

Purpose: To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA.

Patients and methods: This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the UK Clinical Practice Research Datalink (CPRD) Aurum database from 2012 to 2019. Poisson regression models were used to estimate the IRR for AMI, stroke, and MACE in users of COPD medications versus LABA, adjusting for clinically relevant covariables.

Results: The study included 11,121 new users of aclidinium, 4804 of aclidinium/formoterol, 56,198 of tiotropium, 23,856 of other LAMA, 17,450 of LAMA/LABA, 70,289 of LABA/ICS, and 13,716 of LABA. During periods of continuous medication use after initiation (current use), crude incidence rates per 1000 person-years for AMI ranged from 8.7 (aclidinium/formoterol) to 12.4 (LAMA/LABA), for stroke ranged from 4.8 (aclidinium/formoterol) to 7.2 (LAMA/LABA), and for MACE ranged from 13.5 (aclidinium/formoterol) to 19.3 (LAMA/LABA). Using LABA as reference, adjusted IRRs [95% confidence intervals] were close to 1 for all study drugs for AMI (lowest for aclidinium/formoterol, 0.95 [0.60-1.52], and highest for LAMA/LABA, 1.23 [0.91-1.67]), stroke (lowest for aclidinium/formoterol, 0.64 [0.39-1.06], and highest for tiotropium, 1.02 [0.81-1.27] for tiotropium) and for MACE (lowest for aclidinium, 0.93 [0.75-1.16], and highest for LAMA/LABA, 1.24 [0.97-1.59]).

Conclusion: Risks of AMI, stroke, and MACE in current users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, LAMA/LABA, or LABA/ICS were similar to the risks among current users of LABA.

Keywords: LAMA; United Kingdom; aclidinium; acute myocardial infarction; stroke.

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / therapeutic use
  • Adrenergic beta-2 Receptor Agonists / adverse effects
  • Adult
  • Bronchodilator Agents / adverse effects
  • Cohort Studies
  • Drug Therapy, Combination
  • Formoterol Fumarate / adverse effects
  • Humans
  • Muscarinic Antagonists / adverse effects
  • Myocardial Infarction* / chemically induced
  • Myocardial Infarction* / diagnosis
  • Myocardial Infarction* / epidemiology
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Pulmonary Disease, Chronic Obstructive* / epidemiology
  • Risk Assessment
  • Stroke* / diagnosis
  • Stroke* / epidemiology
  • Tiotropium Bromide / adverse effects

Substances

  • Adrenal Cortex Hormones
  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Muscarinic Antagonists
  • Formoterol Fumarate
  • Tiotropium Bromide

Grants and funding

This study was performed under a research contract between RTI Health Solutions (RTI-HS) and AstraZeneca and was funded by AstraZeneca. The contract provides the research team independent publication rights. The sponsors had no role in the data collection or analysis; however, in line with the Guideline on Good Pharmacovigilance Practices: Module VIII: Post-authorisation Safety Studies of the European Medicines Agency, the sponsors had the opportunity to view the results and interpretations included in the manuscript and provide comments before submission of the manuscript for publication.