3F-03 - Tiotropium Initiation and Dementia Risk in Older Adults with Chronic Obstructive Pulmonary Disease: A Population-Based Cohort Study

Background: Long-acting muscarinic antagonists (LAMAs) such as tiotropium are inhaled anticholinergic bronchodilators; however, it has been controversial whether LAMAs should be included in the anticholinergic burden scale, a predictor of cognitive decline. Clinical evidence regarding the relationship between LAMAs and dementia risk has been limited.

Objectives: To examine whether tiotropium initiation is associated with dementia risk in older adults with chronic obstructive pulmonary disease (COPD).

Methods: This population-based study utilized health administrative databases in Ontario, Canada. An active-comparator new-user cohort design was used to reduce confounding by indication. Residents aged ≥66 years who initiated tiotropium monotherapy or a long-acting β2-agonist plus inhaled corticosteroid (LABA-ICS) with COPD and without prevalent dementia, from September 4, 2004 to February 29, 2012, entered this cohort study. A 1-year lag time was used to mitigate potential reverse causation and to account for disease latency. The exposure definition used an intention-to-treat approach to mitigate informative censoring. To compromise between exposure misclassification and dementia as a chronic outcome, individuals were followed for a maximum of 10 years from drug initiation. Incident dementia was defined using a validated algorithm (99.1% specificity; 80.4% positive predictive value). Propensity score fine stratification weights for an average treatment effect were used to adjust for baseline covariates. Cause-specific hazard ratios (HR) with death as a competing risk and their confidence intervals (CI) were estimated using weighted Cox models.

Results: Among 30,960 tiotropium monotherapy and 19,530 LABA-ICS initiators (mean age 75.1 years; 53.3% male), over a median follow-up of 7.59 years from treatment initiation, tiotropium monotherapy vs LABA-ICS initiation showed a 9% higher dementia risk (HR [95% CI]: 1.09 [1.04-1.14]; incidence rates: 29.6 vs 27.4 events per 1,000 person-years). In the subgroup aged 66-74 years, tiotropium monotherapy was associated with a 18% higher dementia risk (1.18 [1.09-1.27]; 18.0 vs 15.5). In the male subgroup, tiotropium monotherapy was associated with a 12% higher dementia risk (1.12 [1.04-1.20]; 28.1 vs 25.3). No significant associations were observed among adults aged ≥75 years (1.05 [0.995-1.12]; 46.1 vs 44.0) or females (1.06 [0.998-1.14]; 31.3 vs 29.6). The results were consistent across sensitivity analyses.

Conclusions: Tiotropium initiation is associated with a modestly higher risk of dementia in older adults with COPD, suggesting that tiotropium may exhibit weak central anticholinergic effects in humans.