Risk of delirium associated with antimuscarinics in older adults: A case-time-control study

Older adults are at an increased risk of delirium because of age, polypharmacy, multiple comorbidities and acute illness. Antimuscarinics are the backbone of the pharmacological management of overactive bladder. However, the safety profiles of antimuscarinics vary because of their dissimilarities to muscarinic receptor-subtype affinities and are associated with differential central anticholinergic adverse effects.

This study aimed to examine delirium risk in new users of oxybutynin and solifenacin in older adults (≥ 65 years). In the secondary analyses, we examined the risk of delirium by type and dose of antimuscarinic.

We applied a case-time-control design to investigate delirium risk in older adults who started taking oxybutynin and solifenacin. We used a nationwide inpatient hospital data (2005-2016), National Minimum Data Set, maintained by the Ministry of Health, New Zealand (NZ), to identify older adults with a new-onset diagnosis of delirium. Eligible patients were older adults aged 65 at entry into the cohort on 1/1/2006. We used dispensing claims data to determine antimuscarinic treatment exposure. The antimuscarinic included in the study were new users of oxybutynin and solifenacin. These two antimuscarinics are subsidised by the Pharmaceutical Management Agency and are the most frequently used antimuscarinic in NZ. A conditional logistic regression model was used to compute matched odds ratios (MORs) and 95% confidence intervals (CIs). In the case-time-control design, we made separate analyses to evaluate the dose-response risk of delirium.

We identified 4818 individuals (mean age 82.14) from 2005 to 2015 with incident delirium and were exposed to at least one of the antimuscarinic of interest. The case-time-control matched odds ratio (MOR) for delirium with oxybutynin was (2.06, 95% confidence interval [CI] 1.07-3.96). Solifenacin was not associated with delirium (0.89 95%CI 0.64-1.23). In the sensitivity analyses, the case-time-control MOR for delirium using a shorter risk period (0-3 days) did not change the results. The dose-response risk of delirium was significant for oxybutynin (0.05, 95%CI 0.02-0.08) but not for solifenacin (-0.01, 95%CI -0.03 to 0.00). In addition, in the subgroup analyses, a statistically significant association of delirium was found for oxybutynin but not for solifenacin in the non-dementia cohort (2.11,95% CI 1.08-4.13) and the dementia cohort (1.25, 95%CI 0.05-26.9).

The study found that oxybutynin but not solifenacin is associated with a risk of new-onset delirium in older adults. The higher blockade of M1 and M2 receptors by oxybutynin is likely to contribute to delirium than solifenacin, which is highly selective for the M3 receptor subtype. Therefore, the treatment choice with an M3 selective agent must be given due consideration, particularly in those with pre-existing cognitive impairment.