Anticholinergic (Ach) medications, a mainstay in the treatment of overactive bladder (OAB), are increasingly linked to incident dementia. Beta-3 agonists (B3A) have emerged as an alternative with a more favorable side-effect profile, especially in elderly patients. This study evaluated whether treating OAB with B3A instead of Ach is cost-effective, accounting for the long-term clinical and economic impact of Ach-associated dementia.
A cost-effectiveness analysis was conducted from the health care sector perspective using a Markov microsimulation model comparing Ach and B3A over a 15-year horizon. Model inputs included costs, utilities, and probabilities of health states and adverse events associated with untreated OAB, pharmacotherapy, and minimally invasive therapies. Health states transitioned between untreated OAB, Ach or B3A, minimally invasive therapy, and dementia. Analysis was performed with TreeAge.
Over 15 years, total health care costs were $97,000 for Ach versus $90,961 for B3A, and total QALYs were 8.65 versus 8.79, respectively. Sensitivity analysis revealed that B3A alone, compared to Ach alone or Ach followed by B3A, is the dominant strategy, and this held when inputs were varied across their ranges.
B3A are cost-saving and more effective than Ach for OAB, largely driven by the elevated dementia risk associated with Ach exposure and the substantial costs and diminished quality of life inherent to dementia. Although clinical guidelines favor eliminating step therapy, many payers still mandate an Ach trial before approving B3A. The long-term burden of Ach-associated dementia exceeds the lower upfront cost of Ach, making B3A more cost-effective overall.
Commentary by Dr. George Bou Kheir
Cognition and the long-term value of OAB pharmacotherapy
The pharmacological management of overactive bladder (OAB) has evolved with the introduction of β3-adrenoceptor agonists, yet antimuscarinic agents remain widely used. Alongside differences in tolerability and persistence, increasing attention has focused on the potential association between cumulative anticholinergic exposure and cognitive impairment and dementia. The cost-effectiveness analysis presented by the authors introduces this question into another domain: how does incorporating potential long-term cognitive outcomes affect the estimated economic value of OAB pharmacotherapy?
Using a Markov microsimulation over a 15-year horizon, the authors compare antimuscarinic and β3-agonist treatment from a U.S. healthcare payer perspective, explicitly incorporating dementia as a health state [1]. Within the assumptions of their model, β3-agonist treatment generated slightly more quality-adjusted life years (QALYs) at a lower overall healthcare cost and was therefore dominant over antimuscarinic treatment. Initial antimuscarinic therapy followed by transition to a β3-agonist was similarly dominated by initial β3-agonist treatment.
Previous economic evaluations have primarily incorporated treatment efficacy, persistence and relatively immediate adverse events. Cognitive outcomes are more difficult to model: they may occur years after exposure, have multifactorial causes and generate healthcare consequences extending beyond the period of OAB treatment. Their inclusion therefore changes both the time horizon and the conceptual framework of pharmacoeconomic evaluation.
There is an expanding epidemiological literature associating anticholinergic exposure with incident dementia, including studies specifically evaluating bladder antimuscarinics. This is particularly relevant in OAB, where prevalence increases with age and treatment often occurs in the context of polypharmacy and pre-existing anticholinergic burden. However, translating such associations into a health-economic model is not simple. Most available evidence is observational, and residual confounding, reverse causation and protopathic bias remain possible [2]. Lower urinary tract symptoms may themselves accompany neurological disease before a formal diagnosis, complicating interpretation of temporal associations between OAB treatment and subsequent cognitive decline.
Antimuscarinics should also not necessarily be considered a homogeneous exposure. Differences in blood–brain barrier penetration, receptor characteristics, pharmacokinetics, dose and treatment duration may be relevant to cognitive risk. Moreover, the anticholinergic burden attributable to an OAB medication represents only part of a patient’s cumulative exposure. These considerations become important when an epidemiological association is converted into a transition probability applied over many years.
This is particularly relevant to the present study because dementia-related utility was the most influential parameter in sensitivity analysis. The model can therefore be viewed as addressing a conditional question: if antimuscarinic exposure contributes to dementia risk to the extent represented by the selected epidemiological inputs, what are the long-term economic consequences? Under those assumptions, incorporating dementia is sufficient to offset the higher acquisition cost of β3-agonists and change the relative economic position of the two treatment strategies.
The U.S. setting provides an informative example. Step-therapy policies may require treatment with one or more lower-cost antimuscarinics before reimbursement of a β3-agonist. Such policies illustrate a tension between short-term pharmaceutical expenditure and long-term healthcare costs. However, the population-level savings projected by the authors remain model-based estimates rather than expected savings following a change in prescribing policy. They depend on assumptions regarding causality, treatment duration, adherence, dementia incidence and healthcare costs.
Future analyses could refine this approach by considering individual antimuscarinic agents rather than a class effect, cumulative dose and duration, concomitant anticholinergic burden and baseline cognitive vulnerability. Causal-inference approaches using longitudinal datasets may also help distinguish treatment-related effects from patient-related variables including ageing, neurological disease, and polypharmacy. Similar analyses across different European healthcare systems would establish whether the conclusions remain robust under different cost and reimbursement structures.
The study therefore contributes more than a comparison between antimuscarinics and β3-agonists. It highlights a challenge in evaluating chronic OAB treatment: how should potential outcomes occurring years after treatment initiation be incorporated into decisions made today? As the evidence linking anticholinergic exposure and cognition continues to evolve, determining the strength and causality of that relationship will remain essential. In parallel, health-economic models will need to consider whether conventional short-term outcomes adequately capture the value and potential downstream consequences of long-term LUTS treatment.