Tiotropium Initiation and Dementia Risk in Chronic Obstructive Pulmonary Disease

Importance: Long-acting muscarinic antagonists (LAMAs), such as tiotropium, are inhaled anticholinergic bronchodilators. However, there is limited clinical evidence examining whether LAMAs may have clinically meaningful central anticholinergic effects, such as increased dementia risk. Objective: To determine the association between tiotropium initiation and dementia risk in older adults with chronic obstructive pulmonary disease (COPD). Design, Setting, and Participants: This population-based, active-comparator, new-user cohort study used linkable administrative databases from Ontario, Canada, with a target trial emulation framework. The cohort included new users of tiotropium monotherapy or a long-acting β2-agonist plus inhaled corticosteroid (LABA-ICS) who were 66 years or older with COPD and without dementia, from September 4, 2004, to February 29, 2012. The follow-up period was up to 10 years from treatment initiation. Analyses were conducted from May 13, 2024, to March 6, 2025. Exposures: Tiotropium monotherapy initiators were compared with LABA-ICS initiators. The primary analysis used an intention-to-treat exposure definition. Main Outcomes and Measures: Incident dementia was determined using a validated algorithm. A 1-year lag time was implemented to mitigate reverse causality and to account for disease latency. Cause-specific hazard ratios (HRs) with death as a competing risk were obtained from Cox models with propensity score fine stratification weights. Weighted incidence rate differences (IRDs) per 1000 person-years were calculated. Results: Among 30 960 tiotropium monotherapy initiators and 19 530 LABA-ICS initiators, the mean (SD) age was 75.1 (6.7) years and 46.7% were female. Over a median (IQR) follow-up period of 7.59 (3.91-10.0) years from treatment initiation, tiotropium monotherapy vs LABA-ICS initiation was associated with a small increase in dementia risk per 1000 person-years (incidence rates, 29.6 [95% CI, 28.8-30.4] vs 27.4 [95% CI, 26.4-28.3]; IRD, 2.3 [95% CI, 1.0-3.5]; HR, 1.09 [95% CI, 1.04-1.14]). The secondary as-treated analysis showed no significant association per 1000 person-years (incidence rates, 24.1 [95% CI, 22.2-26.0] vs 21.4 [95% CI, 18.5-24.3]; IRD, 2.7 [95% CI, -0.8 to 6.1]; HR, 1.11 [95% CI, 0.93-1.32]). Conclusions and Relevance: In this cohort study, among older adults with COPD, the small absolute rate increase in incident dementia associated with tiotropium monotherapy vs LABA-ICS was of questionable clinical importance, particularly when weighed against the established clinical benefits of tiotropium.