Hypothesis / aims of study
Older (>65y old) patients with overactive bladder (OAB) have been shown to have a differential response to younger patients in several clinical trials of antimuscarinic agents[1, 2]. Older patients appear to require higher dosing to achieve maximum benefit from their medications. Older patients are also more likely to experience treatment emergent adverse events than younger people, but may tolerate these in order to achieve optimal benefit. Given the reported association between high anticholinergic load in older people and cognitive adverse events from observational studies [3], this study examined the response to treatment with fesoterodine in older patients and explored any relationship with change in Mini Mental State Examination (MMSE) scores associated with that response, hypothesizing that those with higher dose exposure may well experience a better symptom response but may be more likely to suffer an adverse cognitive effect.
Study design, materials and methods
Data from 2 randomized, placebo controlled phase IV clinical trials of flexibly dosed fesoterodine over 12 weeks duration (A0221045, A0221049) which prospectively collected data on men and women with OAB ≥65y formed the dataset for this study. Analyses were based on the Full Analysis Set (FAS) which included all subjects who took at least one dose of assigned study drug and contributed data to at least one baseline and post-baseline efficacy assessment with baseline value of the outcome variable > 0. MMSE scores were collected at baseline and end of study. The MMSE comprises 11 items across 6 domains and includes such items as recalling the year, correctly identifying a familiar object like a pencil, counting backward, and writing a sentence. The measure has a standardized delivery and scoring system, resulting in scores ranging from 0 to 30 with higher scores indicating less impairment. Change in MMSE score was expressed as percentage change between baseline and week 12 and was compared to percentage change in disease variables (below) between baseline and week 12.
At week 12, the proportion of subjects achieving a 100% and 50% reduction in urinary urgency (UU) episodes/24h and urinary urgency incontinence (UUI) episodes/24h (where baseline UUI episodes ≥2) was calculated. The proportion of subjects achieving a 100% reduction in Nocturnal Micturition Frequency/24h (NMF) (where baseline NMF episodes>1 and 100% resolution was defined as N≤1 at Week 12, Daytime Micturition Frequency (DMF)/24 h (100% resolution was defined as DMF < 8/24h) and the combination of the 3 symptoms, reduction in all of urgency, 24 hr frequency and UUI were derived. To explore any correlation between change in diary episodes and MMSE, heatmap plots of change from baseline in MMSE at 12 weeks vs percent change from baseline in urgency, urgency incontinence, NMF and DMF and Spearman correlation coefficients for each endpoint were calculated.
The frequency of all causality treatment emergent adverse events recorded during the included studies was expressed. Comparisons of responder rates between treatment groups were made with the Cochran-Mantel-Haenszel row mean scores test with modified ridit scoring (Van Elteren test), stratified by covariates.
Results
There were 673 patients treated with fesoterodine and 674 patients treated with placebo, 93.9% patients were white. Demographic details are shown in Table 1. The proportion of patients with a 50% response in UUE/24h and UUI/24h is shown in table 1. The proportion of patients with 100% response to each OAB symptom at 12 weeks is shown in Figure 1. Proportional response to fesoterodine compared to placebo reached statistical significance (p<0.05) in all single OAB symptoms. The proportion of patients with 100% response in all symptoms combined, was not statistically different between groups. Percentage change in MMSE score was not significantly associated with percentage change in any disease related variable over the 12-week period. (Spearman’s rho - UUE/24h, r=0.018; UUI/24h, r=0.052; DMF, r=0.013; NMF, r=-0.033, all p>0.05). A representative heat map of percentage change in MMSE score versus UUI/24h is shown in figure 2. Five percent of placebo treated patients and 11.7% fesoterodine treated patients discontinued their medication due to adverse events. Dry mouth occurred in 29.6% fesoterodine and 5.6% placebo treated patients and constipation was reported by 9.8% fesoterodine treated and 3.3% placebo treated patients.
Interpretation of results
At 12 weeks, flexibly dosed fesoterodine led to greater response than placebo in OAB disease related variables as previously reported. Resolution of all OAB symptoms in combination was virtually unachievable, something which may be clinically useful to inform patients when discussing expectations. Previous studies have shown that only a minority of women and older people seek such a response. There was no relationship between magnitude of response in OAB symptoms and change in MMSE score for any OAB symptom. Data from the source trials revealed that a majority of older people ended their study on the higher, 8mg, dose of fesoterodine. Reassuringly, this does not appear to be related to any increased likelihood of cognitive decline over the 12 weeks study. The data are limited by their short-term nature, the characteristics of the participating patients and the sensitivity of MMSE scores to cognitive change in this context, but largely these data are reassuring.