Introduction
Overactive bladder (OAB) is defined by symptoms of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection (UTI) or other obvious pathology [
1]. This condition is estimated to affect 12–17 % of adults in Europe and the USA [
2‐
5]. OAB is associated with anxiety and depression [
6‐
8], impairment of work productivity [
9], and daily activities [
10‐
12]. It is therefore associated with detrimental effects on health-related quality of life (HRQoL) [
13]. Indeed, the severity of urgency urinary incontinence has been shown to be a predictor for HRQoL [
14].
Clinical trials of treatments for the symptoms of OAB have traditionally relied on objective outcome measures to evaluate treatment efficacy, of which the most commonly used are those recorded in a patient bladder diary, namely micturition frequency, number of incontinence and urgency episodes in a 24 h period, number of nocturia episodes per 24 h, and volume voided per micturition [
15,
16]. However, these endpoints say little about the impact that symptoms have on the patient’s quality of life (QoL) [
17]. Indeed, it has been reported that improvements in objective outcomes do not necessarily correlate with improvements in subjective outcomes, that is, they do not necessarily translate into improvements in HRQoL [
15,
16]. Consequently, there is a growing appreciation of the need to understand health outcomes from the patient’s point of view [
18‐
21], particularly for the treatment of chronic debilitating conditions such as OAB, for which treatment is often aimed at symptom management rather than cure. The International Continence Society recommends that QoL measures be evaluated in the assessment of therapeutic interventions for the management of the symptoms of OAB [
22].
A patient’s likelihood of persisting with a treatment for OAB is related to their satisfaction with that treatment [
23]. Improvements in objective measures, such as micturition frequency, without a concomitant improvement in patient-reported measures of HRQoL, may not be sufficient to persuade the patient to persist with treatment. Indeed, improvements in objective outcomes achieved with common OAB drugs have typically not translated into long-term persistence; persistence rates ranging from 8 to 29 % have been reported in studies with at least 1 year of follow-up [
24‐
27]. On the other hand, statistically significant improvements from baseline in the patient perception of bladder condition (PPBC) score have been seen in an open-label study of darifenacin along with treatment satisfaction for 85 % of patients [
28].
Mirabegron is the first in a new class of agents—the β
3-adrenoceptor agonists—to be approved for the treatment of OAB. In addition to objective bladder diary outcome measures, a range of PROs were evaluated in three randomized, double-blind, placebo-controlled, 12-week Phase III clinical trials (Studies 046 (NCT00689104) [
29], 047 (NCT00662909) [
30], and 074 (NCT00912964) [
31]). Co-primary (objective) outcome measures in all three studies were change from baseline to final visit in mean number of micturitions per 24 h and mean number of incontinence episodes per 24 h. Patient-reported outcomes (PROs) included the overactive bladder questionnaire (OAB-q), the PPBC, and the treatment satisfaction visual analog scale (TS-VAS). In all three Phase III studies, and in a pre-specified, pooled analysis of the three studies [
32], mirabegron 50 mg once daily resulted in statistically significant improvements from baseline to final visit versus placebo on both co-primary outcomes. It also resulted in a statistically significant improvement from baseline to final visit compared with placebo on PPBC as well as on the symptom bother scale and total HRQoL of the OAB-q in all three studies and the OAB-q subscales of coping and concern in Studies 046 and 047. Statistically significant improvement relative to placebo in the OAB-q subscale of sleep was also reported with mirabegron 50 mg in Study 047. In the pooled analysis, the only PRO reported was the TS-VAS; this too showed a statistically significant improvement from baseline to final visit for mirabegron 50 mg versus placebo. Analysis of the pooled data has also shown greater improvement in the EQ-5D utility score with mirabegron 50 mg compared with placebo and tolterodine [
33].
This paper presents the results of post hoc analysis conducted on the large pooled mirabegron 50 mg and placebo data sets described above to determine correlations between various objective and subjective outcome measures utilized in the three Phase III trials. (The 25 mg dose was not evaluated in this post hoc analysis as it was used in Study 074 only and hence was not part of the pooled analysis.) Data showing the effects of mirabegron 50 mg on measures of HRQoL are also presented. In a novel approach to understanding these data, responder analyses were performed to assess the proportion of patients who were simultaneously responders for incontinence episodes and micturitions along with one or two different PROs at final visit. The aims were twofold: firstly, to understand how improvements in objective measures with mirabegron 50 mg correlate with the patient’s experience as measured by validated, standard PRO instruments and secondly, to understand how improvements in different PRO outcomes correlate with one another. This is of interest because PROs assess different components of the response of patients, resulting in heterogeneity in responsiveness to treatment effect.
Discussion
These data extend what has been previously published: in a pooled analysis of three 12-week Phase III studies, mirabegron 50 mg not only resulted in statistically significant improvements versus placebo in change from baseline to final visit in the objective outcomes of mean number of incontinence episodes and mean number of micturitions per 24 h, but also resulted in statistically significant improvements versus placebo in change from baseline to final visit in PPBC, the OAB-q symptom bother scale, OAB-q total HRQoL, and OAB-q subscales of coping, concern, and sleeping, but not social interaction. The social interaction subscale has traditionally been the least responsive of the OAB-q subscales to improvement in patients’ wellbeing, so these results are not surprising [
35,
36].
The improvements produced by mirabegron 50 mg on PROs were also manifest in the proportion of subjects in whom the change from baseline exceeded the MID defined for both the OAB-q (10 points) and PPBC (1 point) instruments. Indeed, two-thirds of subjects who received mirabegron 50 mg experienced a change in the OAB-q symptom bother scale that exceeded the MID for that scale (10 points). The MID values for OAB-q have been related to changes in degrees of disease symptomatology that are directly relevant to the patient’s experience of the disease, such as resolution of incontinence. Hence, the results demonstrate the meaningfulness of the observed therapeutic benefit experienced by the patient.
There was a significant correlation between change from baseline in PPBC and that in the OAB-q symptom bother scale and OAB-q total HRQoL. Moreover, these correlations were large (0.60 and −0.62) [
42] and similar to those between PPBC, OAB-q symptom bother scale, and OAB-q HRQoL reported by Coyne and co-workers [
43] in a similar post hoc analysis of data from a 12-week open-label trial of tolterodine extended release. These results indicate directional consistency in the response of these PROs to mirabegron 50 mg.
Incontinence is a major symptom of OAB, occurring in about one-third of patients, and is associated with significant morbidity, reduction in QoL, and serious limitations to activities of daily living [
44]. QoL scores in OAB patients with incontinence have been shown to be consistently lower than in OAB patients without incontinence [
44]. A statistically significant difference between mirabegron 50 mg and placebo in the percentage of patients who achieved a 50 % or greater reduction in incontinence frequency at final visit has been seen previously [
32]. In the post hoc analyses described here, the unique approach was taken to identify the proportion of patients who
simultaneously achieved a 50 % or greater reduction in incontinence frequency at final visit and the MID in one or two PROs. In all the analyses conducted, mirabegron 50 mg resulted in statistically significantly higher composite responder rates than placebo. Moreover, improvements in both incontinence and micturition frequency were statistically significantly correlated with improvements in each of PPBC, the OAB-q symptom bother scale, and OAB-q total HRQoL. These correlation coefficients were mostly of moderate magnitude (0.30–0.49) [
42] and, regardless of which PRO was examined, were similar for incontinence and micturition frequency. A number of studies have demonstrated the favorable effects of several antimuscarinics on a number of different QoL measures [
45‐
49] and a small to moderate, but statistically significant correlation between improvement in number of urgency urinary incontinence episodes and PPBC has been reported in a 12-week trial of tolterodine extended release [
50]. However, no studies of antimuscarinics have evaluated composite responder rates as done here.
In conclusion, it appears that the improvements in objective outcome measures seen with mirabegron 50 mg are mirrored by statistically significant improvements in the clinically relevant PRO measurements of OAB-q total HRQoL, PPBC, and OAB-q symptom bother scale. Moreover, there is directional consistency in the effect of mirabegron 50 mg across the disparate domains measured by various objective outcomes and PROs. Thus, improvement in objective outcomes translates into a meaningful clinical benefit; the OAB-q and PPBC appear to provide a clinically relevant perspective on OAB management, and the objective outcomes of incontinence and micturition frequency appear to be adequate proxies of patient experience. The results bolster the view that mirabegron may be a good treatment option for OAB patients as improvements in HRQoL measures are likely to be reflected in high patient satisfaction. Nonetheless, studies that specifically evaluate patient satisfaction are necessary to confirm this suggestion. In addition, studies examining patient adherence with mirabegron are required; patient adherence with antimuscarinics, the current mainstay of treatment for OAB, is poor, largely due to intolerable side effects, and it will be interesting to see whether mirabegon’s favorable effects on QoL measures translate into good adherence levels.