Background
Overactive bladder (OAB) is a syndrome, comprising urinary urgency, usually accompanied by increased daytime frequency and nocturia, with or without urinary urgency incontinence, in the absence of urinary tract infection or other obvious pathology [
1,
2]. The prevalence of OAB increases with age and is expected to affect 1 in 10 people by 2018 [
3]. The chronic nature of OAB and severity of symptoms makes it problematic for many patients, often resulting in significant deterioration in quality of life (QoL), depression and social isolation [
4]. Significant economic consequences are associated with OAB as a result of health resource costs and decreased work productivity [
4].
Patients with OAB tend to seek treatment once their QoL is affected, and are more likely to persist with their medication if they perceive meaningful improvements in QoL [
5]. This underlies the importance of evaluating the benefits of a treatment not only according to objective changes in bladder parameters (e.g. micturition frequency, incontinence episodes) but also via subjective outcomes related to QoL, perception of symptoms, and general well-being. Validated bladder health questionnaires include the OAB-questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC), and OAB-Treatment Satisfaction (OAB-S) questionnaire. The OAB-q is useful for assessing treatment effects on various aspects of QoL such as social interaction, coping, sleep, and the extent of bother associated with symptoms [
6,
7], and the single-item PPBC evaluates patients’ perception of their current bladder problems [
8]. However, neither the OAB-q or PPBC explores additional factors related to patient satisfaction with their medication. The OAB-S was developed to measure the ‘multidimensional concept’ of treatment satisfaction over a number of domains, including 5 independent scales (OAB Control Expectations, Impact on Daily Living with OAB, OAB Control, OAB Medication Tolerability, and Satisfaction with OAB Control) and 5 single-item overall assessments (Patient’s Fulfillment of OAB Medication Expectations, Interruption of Day-to-Day Life Due to OAB, Overall Satisfaction with OAB Medication, Willingness to Continue OAB Medication, and Improvement in Day-to-Day Life Due to OAB Medication) [
9].
Communicating the clinically meaningful benefits of treatment to the patient can be simplified through the use of responder analyses [
10]. These clinically meaningful changes are often expressed as specific differences or thresholds, known as a minimally important difference (MID). The MID is assessed at the individual level of analysis such that changes consistent in magnitude with the MID in individual PROs over time are interpreted as a treatment benefit in the population [
10]. The MID is defined as “the smallest difference in score in the domain of interest that patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive costs, a change in patient management” [
11]. This approach is used to categorize patients into two distinct groups based on those who attain a treatment benefit in the PRO (‘responder’) vs those who do not attain a treatment benefit (‘non-responder’). For PROs in which no MID has been established, responders to OAB treatment have been variably defined and have included positive response categories to specific questionnaire items [
12].
Mirabegron (β3-adrenoceptor agonist) and tolterodine (antimuscarinic) belong to the two classes of oral pharmacotherapies used to treat OAB. Both drugs have similar efficacy in decreasing OAB symptoms of urinary urgency, frequency and incontinence. The different mechanism of action of mirabegron, however, is associated with a lower frequency of specific antimuscarinic side effects, such as blurred vision and dry mouth [
13]. Dry mouth is the most frequent and bothersome side effect reported with antimuscarinics, [
14] and one of the main reasons patients discontinue antimuscarinic treatment [
15].
Potential differences in tolerability between antimuscarinics and mirabegron may confer clinically meaningful improvements in health-related QoL (HRQoL), treatment satisfaction, and persistence. Medication tolerability can be an issue in both treatment-experienced and treatment-naïve patients; however, the treatment-naïve patients have lower rates of persistence at 12 months, [
16] which may be a consequence of higher treatment expectations or a lower tolerability threshold compared with treatment-experienced patients.
In clinical practice, the successful management of OAB demands greater focus on demonstrable benefits in PROs rather than relying solely on reductions in bladder symptoms. Each patient is different in terms of how he or she experiences symptoms and responds to treatment, according to his or her own priorities, expectations, and attitudes. Therefore, a comprehensive approach to evaluating efficacy and tolerability that considers the impact of symptoms on the individual’s experience and lifestyle may be predictive of long-term persistence [
17].
A crossover study design is a methodology for comparing two or more therapies in the same patient and obviates the need to account for inter-patient variability. PREFER was a phase IV, crossover trial in patients with OAB in which a statistically significantly higher OAB-S Medication Tolerability score (the primary endpoint), implying better tolerability, was demonstrated with mirabegron vs tolterodine extended release (ER) 4 mg [
18]. Mirabegron was also associated with significantly fewer anticholinergic side effects [
18]. However, improved tolerability did not translate into preference for mirabegron (the secondary endpoint). Herein PROs and corresponding responder rates from the PREFER study are reported to further explore potential treatment differences and identify outcomes that may be predictive of treatment success.
Discussion
The chronic symptoms that characterize OAB have a negative impact on patients’ overall wellbeing, and can manifest as more serious complications such as depression and psychological distress [
4]. It is therefore imperative to measure treatment outcomes that reflect how the patient perceives changes in their symptoms and subsequent changes to their daily life. This approach is also more likely to help differentiate OAB treatments, as objective measures of bladder symptoms are usually of a similar magnitude between antimuscarinic agents and mirabegron [
13].
In PREFER, which consisted of a treatment-naïve population characterized by moderate levels of symptom bother and disruption to daily activities, the average improvement over time in PROs, as measured by the OAB-S, OAB-q and PPBC questionnaires, were comparable during treatment with mirabegron vs tolterodine ER with the exception of the OAB-S Medication Tolerability score [
18]. Although most PROs improved over time, both treatments were similarly associated with a decrease in the OAB-S assessment of Willingness to Continue OAB Medication. The magnitude of change from baseline in most of these scores is either consistent with or greater than changes seen in studies that include non-naïve users [
12,
24].
Improvements in the OAB-S questionnaire were evident after 4 weeks of treatment and included positive changes in daily activities, as reflected by scores related to the daily impact of OAB and interruptions to daily routines, and the patient’s perception of treatment benefits according to scores related to satisfaction with OAB control and OAB medication. Treatment expectations may have been higher, and the tolerability threshold lower, in this treatment-naïve population compared with previously treated patients, which may have contributed to the decrease over time in Willingness to Continue OAB Medication that was observed with both study drugs. In the majority of OAB-S scales, the 4-week results with mirabegron were lower than tolterodine ER, but at 8 weeks mirabegron was associated with higher scores than tolterodine ER. This may have been due to a suboptimal duration of treatment for mirabegron at 4 weeks, or that some patients do not respond to the 25 mg dose.
Similar improvements over time with mirabegron and tolterodine ER were evident for each scale of the OAB-q and PPBC. With the exception of the Social Interaction subscale, each OAB-q scale and subscale was markedly improved after 4 weeks of treatment, and by EoT adjusted baseline changes ranged from 15 to 20 signifying clinically meaningful improvements. The PPBC score was reduced by approximately 1, also considered clinically meaningful, after 4 weeks and continued to improve after 8 weeks by a similar magnitude with both treatments. The rapid improvement in the majority of PROs measured at 4 weeks in PREFER reflects temporal improvements in bladder diary parameters as reported in the previous analysis of PREFER, and is consistent with that seen in placebo-controlled phase III trials [
18,
25,
26].
Although mean OAB-q scores did not appear to differ between treatments, the responder analyses showed clinically meaningful improvements for the majority of patients (> 50%) in each OAB-q scale except Social Interaction. Although not tested for significance, in each subscale the percentage of responders was higher with mirabegron than with tolterodine ER. The percentage of patients achieving the pre-specified responder definition on the OAB-S Medication Tolerability score (≥ 90) was also higher with mirabegron vs tolterodine ER, supporting the finding of the statistically significant difference in the OAB-S Medication Tolerability score in favor of mirabegron, as reported previously [
18]. These responder analyses suggest a greater potential for patients to achieve clinically meaningful improvements in QoL, the perception of their bladder condition, and tolerability with mirabegron.
The magnitude of the improvement in the PROs and the corresponding responder analyses are consistent with subjective endpoints reported in previous phase III studies investigating mirabegron and tolterodine ER [
26,
27]. In a recent placebo-controlled phase III trial investigating PROs, mirabegron 50 mg was associated with significant improvements over placebo for two OAB-q subscales (Coping and Concern) which was not observed with tolterodine ER 4 mg [
28]. Furthermore, the phase III mirabegron study showed greater improvements in presenteeism and greater reductions in absenteeism and overall work impairment than placebo or tolterodine ER 4 mg [
28].
The lack of treatment difference in the average scores on the PROs could be related to the interplay of OAB symptoms and how each individual responds differently according to his or her own priorities, lifestyles and expectations. A real-world evaluation of the OAB-S in older adults starting mirabegron or an antimuscarinic showed similar trends in PRO improvement over time, but without differences between mirabegron and antimuscarinics, despite mirabegron patients being older and having a higher burden of comorbidities and prior treatment [
29]. However, failure of the PREFER study to detect these differences over time may have been due to inadequate adjustment for confounders such as comorbidities and age, which may affect PRO outcomes. The randomized crossover higher order design should have accounted for these potential issues and we do believe that any influence of sequence or period on PROs is unlikely given the lack of a period-by-treatment interaction effect on tolerability scores in the previous analysis of PREFER [
18]. Despite a 2-week washout period, the slight improvement in PRO scores in period 2 is possibly indicative of some carryover effect, despite far greater than 5 half-lives of drug washout. Moreover, the higher order design, whereby sequences in which patients received the same drug twice were included, allowed within-patient estimates of treatment effect irrespective of carryover effect. Also evident from the previous analysis of PREFER was that tolerability was not the main reason patients gave for their preference of medication at the end of the study, with only 24.7% and 18.7% of patients choosing “tolerated better” during treatment as the reason for their preference with mirabegron and tolterodine ER, respectively [
18]. Therefore if patients value improvement in their symptoms over fewer side effects, differences in tolerability are only one piece of the puzzle. The relatively shorter treatment period in this study (8 weeks) compared with most OAB trials (12 weeks) may also have contributed to the lack of treatment differences; for example, patients experiencing side effects such as dry mouth for 8 weeks may not be as bothered as they might after 12 weeks. It is also worth noting that while mirabegron 25 mg demonstrates good efficacy at 4 weeks, maximal efficacy is not reached until 8 weeks and hence the maximal efficacy was reached as the patients were approaching the washout/switch period [
30]. A handheld electronic device was used to record PROs. Although this approach has been shown to improve the accuracy and reliability of recording bladder diary parameters versus a paper diary, [
31] we have not found validation of the PROs used in this study for the electronic device. The electronic recording of the PROs used in this study may be a potential limitation; however, we would have no reason to believe that the instruments would behave differently in the two time periods in a crossover study.
PREFER is the first late-phase OAB clinical trial to utilize a crossover design and explore PROs related to QoL and satisfaction, including responder analyses to assess clinically relevant improvements. By measuring PROs using three validated questionnaires, PREFER presents a comprehensive analysis of the patient’s experience of mirabegron and tolterodine ER treatment during the 20-week study. Combining the multidimensional concept of treatment satisfaction (OAB-S), aspects of QoL, symptom bother and perceptions of bladder condition ensures that the most important components of the patient’s lifestyle and wellbeing is measured following treatment. Despite previously demonstrating a difference in tolerability in favor of mirabegron, which was accompanied by a reduced rate of anticholinergic side effects, there were no differences in average scores over time between mirabegron and tolterodine ER for other scales of the OAB-S, OAB-q and PPBC. However, the proportion of patients achieving clinically relevant improvements in the overall scores for these questionnaires as measured by the MID or patients who were not bothered by the drug side effect was consistently higher with mirabegron than tolterodine ER.
Sample size calculations for PREFER were based on the primary endpoint (OAB-S Medication Tolerability Score), but not for other outcomes. Specifically because the other PROs were exploratory in nature, hypothesis testing of the other PROs was not done. Although multivariate analysis corrected for sex and baseline values was carried out, it is possible that important covariates such as age and comorbidities that may have had an impact were missed. However, other randomized controlled trials that have used other PROs have not controlled for comorbidities, and have found differences [
24].
Phase IV studies of both treatment-naïve and -experienced patients, have demonstrated higher persistence with mirabegron vs antimuscarinics, [
16,
32] which may be a consequence of greater tolerability and preference for mirabegron. The relationship between treatment preference, patient behavior and persistence requires further investigation to determine who derives the most benefit from the different treatments.