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Cristina Rebordosa,1 Estel Plana,2 Annalisa Rubino,3 Jaume Aguado,2 David Martinez,2 Alejhandra Lei,4 Sami Daoud,5 Nuria Saigi-Morgui,1 Susana Perez-Gutthann,1 Elena Rivero-Ferrer1 1Department of Epidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain; 2Department of Biometrics, RTI Health Solutions, Barcelona, Spain; 3Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 4Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 5BioPharmaceuticals Research and Development, Late-Stage Development Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina Rebordosa, RTI Health Solutions, Department of Epidemiology and Risk Management, Av. Diagonal, 605, 9-1, Barcelona, 08028, Spain, Tel +34.93.362.2807, Fax +34.93.760.8507, Email crebordosa@rti.orgBackground: 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: aclidinium, acute myocardial infarction, LAMA, stroke, United Kingdom

Cristina Rebordosa, 1 Estel Plana, 1 Annalisa Rubino, 2 Jaume Aguado, 1 Alejhandra Lei, 3 Sami Daoud, 4 Nuria Saigi-Morgui, 1 Susana Perez-Gutthann, 1 Elena Rivero-Ferrer 1 1RTI Health Solutions, Barcelona, Spain; 2Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 3Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 4BioPharmaceuticals Research and Development, Late-Stage Development Research and Innovation, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina RebordosaRTI Health Solutions, Av. Diagonal, 605, 9-1, Barcelona, 08028, SpainTel +34 93 241 7766Fax +34 93 760 8507Email crebordosa@rti.orgBackground: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium.Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA.Methods: This population-based cohort study included patients with COPD aged ≥ 40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates.Results: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69– 70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53– 1.53) for aclidinium, 1.02 (0.69– 1.51) for tiotropium, 0.86 (0.50– 1.47) for other LAMAs, 1.09 (0.41– 2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS.Conclusion: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA.Keywords: aclidinium, LAMA, heart failure, United Kingdom