Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 4  |  Page : 135-144

Improvement of health-related quality of life in patients with overactive bladder syndrome: A subanalysis of the prospective, noninterventional study BELIEVE in the Greek population


1 Department of Urology, Aristotle University of Thessaloniki, Thessaloniki, Greece
2 Department of Medical Affairs, Astellas Pharmaceuticals AEBE, Athens, Greece

Date of Submission05-Apr-2021
Date of Decision13-Apr-2021
Date of Acceptance27-Apr-2021
Date of Web Publication13-Aug-2021

Correspondence Address:
Apostolos Apostolidis
Department of Urology, Aristotle University of Thessaloniki, 56403 Thessaloniki
Greece
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HUAJ.HUAJ_17_21

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  Abstract 


Objective: The BELIEVE study is a prospective, noninterventional study which was conducted in a real-world setting in Europe and assessed quality of life, treatment satisfaction, healthcare resource utilization, and persistence with treatment in patients with overactive bladder (OAB) syndrome prescribed mirabegron as part of routine clinical practice. We present the results of a subanalysis of the BELIEVE study in the Greek population. Materials and Methods: The primary endpoint was change from baseline in quality of life (QoL) based on the OAB-questionnaire (OAB-q), consisting of the Symptom Bother Scale and health-related QoL (HRQoL). Change from baseline in QoL based on the EQ-5D-5 L health survey, treatment patterns and persistence with treatment, as well as adverse events during the study were also assessed. The duration of the observation period was 12 months. Results: A total of 97 OAB patients from 10 sites in Greece participated in the substudy; 89 completed the OAB-q at baseline and at least at one follow-up visit (Full Analysis Set, mean age 62.7 ± 10.9 years, 86.5% female). At baseline, 73% of patients were “new,” 14.6% were “lapsed,” 9% switched treatment, and 3.4% were on combination treatment. The scores in the Symptom Bother Scale and HRQoL Scale improved significantly from baseline at 10–12 months (−32.4 ± 2.54 and 30.2 ± 2.49, respectively). The EQ-5D subscales confirmed that mirabegron led to an improvement in the HRQoL of patients. At 10–12 months, 72% of patients were continuing on mirabegron treatment for OAB, either as single treatment (60%) or as combination treatment (12%). Mirabegron was well-tolerated, as no serious drug-related adverse events (AEs) were observed, whereas only a small percentage (6.2%) of drug-related AEs resulted in treatment discontinuation. Conclusions: The Greek population subanalysis confirmed the European results of the BELIEVE study. Patients who received mirabegron in a real-world setting showed clinically meaningful improvements in HRQoL. Mirabegron demonstrated a high persistence rate (72% at 12 months), and good tolerability. The overall improvement in HRQoL, particularly in the population continuing to receive mirabegron at 10–12 months, and the low incidence of AEs may have contributed to the high persistence rate.

Keywords: Mirabegron, overactive bladder, persistence with treatment, quality of life


How to cite this article:
Apostolidis A, Petoumenou G, Tzanetakou M. Improvement of health-related quality of life in patients with overactive bladder syndrome: A subanalysis of the prospective, noninterventional study BELIEVE in the Greek population. Hellenic Urology 2020;32:135-44

How to cite this URL:
Apostolidis A, Petoumenou G, Tzanetakou M. Improvement of health-related quality of life in patients with overactive bladder syndrome: A subanalysis of the prospective, noninterventional study BELIEVE in the Greek population. Hellenic Urology [serial online] 2020 [cited 2021 Sep 24];32:135-44. Available from: http://www.hellenicurologyjournal.com/text.asp?2020/32/4/135/323796




  Introduction Top


Overactive bladder syndrome (OAB) is characterized by urinary urgency, with or without urgency incontinence, usually accompanied by frequency and nocturia, in the absence of urinary tract infection or other detectable pathology.[1] According to the EPIC study, the largest to date population-based survey conducted in five European countries, the overall prevalence of OAB symptoms is approximately 12% with similar rates between men and women and seeming to increase with age. Notably, this study further confirmed that most patients with OAB appear to most commonly have a combination of symptoms in both sexes.[2]

Although not life-threatening, OAB syndrome has a negative impact on patient's daily activities, mental health, sexual and family life, and overall quality of life (QoL). The diagnosis and treatment of OAB are largely driven by patient's reporting of symptoms in combination with the physician's assessment. Patient's perception of treatment outcome should be regarded as an important measure of efficacy since the patient himself is the final recipient of the overall treatment benefit (improvement of symptoms, AEs, and effect on daily life).[3],[4],[5] Within the context of assessing the effect of the syndrome on the QoL, several valid and reliable questionnaires have been developed,[6] such as the OAB Symptom Score[7] and the OAB -questionnaire (OAB-q).[8]

Currently, several treatment options are available for OAB (bladder training, behavioral, pharmacological, and surgical treatment),[9] with antimuscarinic agents representing the mainstay of pharmacological treatment.[10] Mirabegron is a b3-adrenoceptor agonist approved for the treatment of OAB, with a mechanism of action different from that of antimuscarinic agents.[10],[11],[12] It is well-tolerated and effective in the treatment of OAB symptoms, such as urinary incontinence and frequency.[13] It demonstrates similar efficacy to most antimuscarinics, but a lower incidence of dry mouth, the most common AEs of antimuscarinics and one of the main reasons for their discontinuation.[12],[14]

Clinical trials with mirabegron have demonstrated improvements in secondary efficacy variables related to QoL using patient self-administered questionnaires (e.g., OAB-q, Patient Perception of Bladder Condition [PPBC], Treatment Satisfaction–Visual Analogue Scale [TS-VAS]).[15],[16] The BELIEVE study is a prospective, noninterventional study, which was conducted in a real-world setting of routine clinical practice in Europe and assessed the QoL, treatment satisfaction, healthcare resource utilization and persistence with treatment in OAB patients prescribed mirabegron as part of routine clinical practice.[17] In this article, we present the results of a subanalysis of the BELIEVE study in the Greek population.

Objective

The primary objective of this subanalysis is to assess the effect of mirabegron on patients' QoL in the Greek population, as recorded by the OAB-q. Secondary objectives include patients' persistence with treatment, prescription status, healthcare resource utilization, as well as safety of treatment.


  Materials and Methods Top


The design and methods of the prospective, noninterventional BELIEVE study have already been published.[17] Overall, 862 OAB patients from eight European countries participated in the study, 97 of whom were from Greece. The BELIEVE study received official approval from the Ethics Committee, as well as other regulatory bodies in all participating countries, in accordance with the country-specific requirements. Patients provided their written consent before their study enrollment.

This sub-analysis was conducted in patients with OAB (males and females aged ≥18 years) from 10 sites in Greece, prescribed mirabegron as part of routine clinical practice. Patients were enrolled in the study before the initiation of mirabegron treatment and were kept under medical observation for 12 months. Patients with mixed urinary incontinence where stress urinary incontinence (SUI) was the predominant symptom, patients at risk of acute urinary retention (at the investigator's opinion), and finally, patients undergoing catheterization were excluded from participation in the study.

Patients were categorized as follows:

  • New: Patient who is treatment-naïve or has not received any pharmacological OAB treatment for ≥2 years
  • Lapsed: Patient who has previously received a prescription for pharmacological OAB treatment, but did not return for a prescription refill >3 months to <2 years from the expected date of refill to the date of enrollment
  • Switched: Patient who has returned to the clinic within 3 months of the due date to refill his prescription and a decision has been independently made by the physician to change his treatment to mirabegron as part of the routine clinical practice
  • Combination treatment: Patient receiving an oral antimuscarinic treatment for OAB at baseline, but the clinician has decided to add mirabegron for additional improvement of OAB symptoms.


The primary endpoint was change from baseline in QoL, as assessed based on the OAB-q. The OAB-q is a valid psychometric questionnaire which has been extensively used in QoL-related research in individuals with OAB. It can be self-administered and consists of 33 items, 8 of which are referring to symptom bother (Symptom Bother Scale) and 25 referring to health-related QoL (HRQoL), sub-divided in the sub-scales Coping, Concern, Sleep, and Social Interaction.[8] The OAB-q was assessed at baseline visit as well as at each visit during the 12-month observation period.

The secondary endpoints were the following:

  • Change from baseline in QoL based on the EQ-5D-5 L. The EQ-5D-5 L is an international standardized, generic instrument for the description and assessment of QoL. It consists of 5 main subscales (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 response levels characterized from no problems to inability to perform the activity. In addition, it contains a VAS, which is used by the patient to self-rate his/her health status
  • Utilization of healthcare resources related to OAB management (type of visit, any medical intervention, inpatient hospitalization, or rehabilitation to manage complications associated with OAB-any selective surgery that had been scheduled before patient-initiated mirabegron was not counted under this case)
  • Treatment patterns and persistence with treatment, and in particular:


    • Treatment patients were switched to and reasons associated with switching
    • Treatment discontinuation and reasons associated with it.
    • Number of treatment days on current treatment.
    • Time from treatment initiation to discontinuation or switching to another treatment.
    • Time from treatment initiation to prescription of additional oral OAB treatment and reasons for combination treatment.


  • Change from baseline in incontinence status. OAB “wet” patients were defined as those having at least one urgency incontinence episode in the 3 days before the visit. SUI and postmicturition dribble were not included in this assessment. OAB “dry” patients were defined as those having no urgency incontinence episodes in the 3 days before the visit
  • AEs reported during the study.


All variables were assessed at baseline visit as well as at each visit during the 12-month observation period.

For the statistical analysis, descriptive statistics were used to summarize all collected information of patients participating in the study. For continuous variables, descriptive statistics included the number of individuals (n), mean (for observed values and absolute changes from baseline), standard deviation (SD), median, minimum, and maximum. Moreover, with regard to the questionnaires' analysis, the standard error and 95% confidence intervals are given for the mean change from baseline. For categorical variables, the number and percentage of individuals by each category were recorded by visit. The number of missing observations was specified for each variable.

The full analysis set (FAS) included all enrolled patients who signed the informed consent form and completed the OAB-q at baseline and at least one follow-up visit. The FAS was regarded as the main analysis set for primary and secondary endpoints, baseline characteristics, disposition, and medical history of patients.

The per-protocol set (PPS) included all patients who received mirabegron for 10–12 months and completed the OAB-q at baseline and at 10–12 months. The safety analysis set (SAF) consisted of all patients who received at least one dose of mirabegron during the study.


  Results Top


Overall, 97 patients from 10 sites in Greece participated in the study, with a mean (± SD) age of 63.4 (±10.8) years and the majority of them being females (n = 83, 85.6%). All 97 patients received at least 1 dose of mirabegron during the study (SAF). Of all patients, 70 (72.2%) were “new,” 10 (10.3%) were “lapsed,” 14 (14.4%) were “switched” and 3 (3.1%) were on combination treatment. The severity of OAB symptoms was evaluated as moderate or as severe by 47 patients (48.5%), respectively.

Fifty-four patients received mirabegron for 10–12 months and completed the OAB-q at baseline and at 10–12 months (PPS). Concomitant medication use (for a disease other than OAB) was reported by 56 patients (57.7%). Ten patients (10.3%) discontinued early from the study (4 were lost to follow-up, 2 due to lack of efficacy, 3 due to AEs, and 1 for “other” reason which was not reported).

Eighty-nine patients with a mean (± SD) age of 62.7 (±10.9) years (77 females, 86.5%) completed the OAB-q at baseline and at least at one follow-up visit (FAS). In the FAS, the severity of OAB symptoms was evaluated as moderate by 44 patients (49.4%) and as severe by 43 patients (48.3%). Sixty-five patients (73%) were “new,” 8 (9%) were “lapsed,” 13 (14.6%) were “switched,” and 3 (3.4%) were on combination treatment.

The most commonly reported medical conditions at baseline were hypertension (FAS 18%, SAF 18.5%), hyperlipidemia (FAS 12.4%, SAF 13.4%), diabetes mellitus (FAS 10.1%, SAF 9.3%), hypothyroidism (FAS 6.7%, SAF 6.2%), osteoporosis (FAS 6.7%, SAF 5.2%), urinary incontinence (FAS 5.6%, SAF 5.2%), pollakiuria (FAS 5.6%, SAF 5.2%), benign prostatic hyperplasia (FAS 4.5%, SAF 3.1%), and nocturia (FAS 3.4%, SAF 3.1%).

The total score in Symptom Bother Scale and HRQoL Scale [Chart 1], [Chart 2], [Chart 3], [Chart 4], [Chart 5] appears to improve from baseline at 10–12 months both in FAS and PPS, and so does the score in OAB-q subscales regarding Coping, Concern, Sleep and Social Interaction [Table 1]. This improvement, defined as a decrease from baseline of at least 10% in Symptom Bother Scale score or an increase from baseline of at least 10% in the other subscales (Minimal Important Difference, MID), was reported in a higher percentage of patients at 10–12 months for both FAS and PPS and was consistently higher for PPS compared to FAS.

Table 1: Improvement (minimal important difference)* from baseline in overactive bladder-q subscales at 2-4 months and 10-12 months (full analysis set and per-protocol set)

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Health status, as described by the EQ-5D-5 L [Chart 6] and the EQ-5D VAS [Chart 7], improved from baseline visit at 10–12 months in the FAS [Table 2], except for the “Self-care” dimension that already had a low symptom score (1.1 ± 0.05) at baseline visit and showed no change at both time-points.

Table 2: Health status based on the EQ-5D-5L health survey and the EQ-5D visual analog scale from baseline to 2-4 months and 10-12 months (full analysis set)

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In total, a very small number of patients visited a healthcare professional due to OAB (9 [10.1%], FAS). Urologists were the most frequently visited healthcare professionals. The overall healthcare resource utilization was minimal, based on examinations performed (such as bladder ultrasound), medical interventions, and hospital visits/admissions, as presented in [Table 3].
Table 3: Utilization of healthcare resources related to the management of overactive bladder in Greece

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Prescription status reveals persistence with treatment, as well as treatment discontinuation and switching patterns. At 10–12 months, 56 patients (72%) in total were continuing on mirabegron treatment for OAB, either as single treatment (47 patients, 60%) or as combination treatment (nine patients, 12%) (FAS). The rest either switched from mirabegron to another OAB treatment (seven patients, 9%) or discontinued OAB treatment completely (15 patients, 19%) [Table 4] and [Chart 8]. The most common reasons for switching or discontinuing mirabegron treatment were resolution/successful treatment of the symptom and medication cost.
Table 4: Summary of prescription status and time on treatment in Greece full analysis set

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Mirabegron was well-tolerated. No serious AEs related to mirabegron were observed. Overall, 23 patients (23.7%) experienced at least 1 AE (31 AEs in total). Eight out of 31 AEs, in six patients (6.2%), were considered as (possibly or probably) related to mirabegron, were of mild or moderate intensity (urinary tract disorders were the most common AEs), and led to permanent drug discontinuation [Table 5] and [Table 6].
Table 5: Overview of adverse events

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Table 6: Adverse events leading to treatment discontinuation

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  Discussion Top


HRQoL has been assessed in large (>400 patients on mirabegron), multicenter, randomized, double-blind studies of[12],[13],[18],[19] or 52-week[20] duration, and in large real-world studies (>1000 patients on mirabegron).[21],[22],[23] In the context of these studies, treatment with mirabegron (50 mg) for 12 weeks in OAB patients resulted in statistically significant improvements in the objective efficacy variables and secondarily, in patient-assessed outcomes compared to placebo.[13],[18],[19] Two-thirds (2/3) of patients who received mirabegron experienced a change greater than the MID (10 points) in the Symptom Bother Scale of the OAB-q, which is indicative of the therapeutic benefit as experienced by patients.[24] The efficacy of mirabegron (50 mg) (as recorded by the OAB-q, PPBC, and TS-VAS questionnaires) appears to be maintained throughout a 12-month period.[20],[25]

In the present subanalysis, an improvement in HRQoL based on OAB-q scores was recorded. These improvements were observed from baseline to 2–4 months, and were subsequently maintained and further increased at 10–12 months of mirabegron treatment (symptom bother scale score −32.4 ± 2.54 and HRQoL scale total score 30.2 ± 2.49) [Table 1] and [Chart 1],[Chart 3]; confirming the positive results of the 52-week randomized trial (−13.1 ± 0.65 and 10.7 ± 0.58, respectively).[20] In addition, a quite high percentage of patients exceeded the MID (70.8% and 64% in the FAS for the total score in the Symptom Bother and HRQoL scales, respectively), demonstrating clinically meaningful improvements.

At this point, it is worth mentioning that the overall European results of the BELIEVE study[17] demonstrated clinically meaningful improvements, but with lower changes at all the subscales of the OAB-q compared to the Greek sub-analysis (e.g., change from baseline at 10–12 months in the Symptom Bother Scale score was −20.7 and MID responders were 52.5%, whereas in the HRQoL Scale were 17.4% and 45.5%, respectively). The baseline characteristics of the participants may have contributed to the differences observed in the results of the Greek analysis in relation to the results of the European analysis. For instance, with regard to the medical history of patients, differences are evident between the two analyses, especially in terms of prescription status and OAB symptoms at baseline. In the Greek sub-analysis, 73% of all patients were “new” and 14.6% were “switched,” while in the European analysis the corresponding percentages were 42.2% and 41.3%, respectively. Moreover, the majority of Greek participants experienced only urgency incontinence (60.7%) and fewer patients experienced urinary frequency/urgency without incontinence (28.1%), nocturia (21.4%), and mixed stress/urgency incontinence (11.2%) [Table 7]. In the European analysis, these percentages were considerably different (44.5%, 30.4%, 47.5%, and 30.5%, respectively). In addition, another difference between the European and Greek participants was observed in the non-OAB medical history. In particular, the majority of all participants in the BELIEVE study (82% in FAS, 81.7% in SAF) had medical conditions (other than OAB) at baseline, whereas this percentage was quite lower in the Greek sub-analysis (49.4% in the FAS, 49.5% in the SAF). Similar differences between the two populations are also observed in the reported conditions.[17]
Table 7: Baseline characteristics of patients in the full analysis set and safety analysis set

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All improvements in the OAB-q scores of this sub-analysis at 10–12 months were greater for the PPS than for the FAS. As far as “Social Interaction” subscale is concerned, changes from baseline to endpoint were lower than those in all other measured subscales, at both the European and Greek results. Similar results have also been reported in a phase III trial, which showed statistically significant improvements with mirabegron compared to placebo in the OAB-q subscales (i.e., “Coping” 16.9 ± 1.1 and “Concern” 18.0 ± 1.0), with the exception of “Social Interaction” (7.4 ± 0.8).[19] These results are not surprising, given that “Social Interaction” generally shows less improvement in relation to the other subscales.[26],[27]

The EQ-5D Health Survey subscales (individual EQ-5D subscales and health status) confirmed that mirabegron led to an improvement of patients' HRQoL. The EQ-5D VAS has also been used as a secondary outcome in 3 phase III trials, where mirabegron resulted in a quicker and superior improvement in HRQoL compared to tolterodine (an antimuscarinic drug).[28]

In addition, a small number of visits to healthcare professionals and interventions associated with OAB management were recorded, demonstrating minimal healthcare resource utilization by Greek participants. These results are consistent with health economic models in the US,[29],[30] Canada,[31] and UK,[32],[33] which indicate that mirabegron is a cost-effective treatment strategy compared to antimuscarinic drugs. Hakimi et al. also observed an improved persistence with mirabegron treatment in routine clinical practice, which is associated with the benefits of reduced healthcare resource utilization compared to antimuscarinic drugs.[34]

Medication persistence and adherence are affected by inadequate efficacy and bothersome side-effects, while their improvement may contribute to successful OAB treatment. In general, reduced persistence and adherence with antimuscarinic treatment for OAB has been observed. In contrast, mirabegron appears to be associated with higher levels of persistence with treatment for OAB in relation to antimuscarinic drugs.[35] In our subanalysis, prescription status showed that 72% of patients (FAS) were continuing on mirabegron treatment (either as single or as combination treatment) at 10–12 months, a fact indicating high persistence, higher than that of the European analysis (53.8%). In addition, our results are in agreement with those from large retrospective real-world studies in Spain[36] and the United Kingdom.[21],[23] In Spain, OAB patients receiving mirabegron experienced longer persistence with treatment than those receiving antimuscarinic drugs (90 vs. 56 days).[36] In a large UK population sample, the mean time to treatment discontinuation was significantly longer for mirabegron compared to antimuscarinic drugs, for example, 169 versus 30–78 days[21] and 101 versus 27–56 days, respectively.[23] Similarly, in a retrospective analysis performed in the US, the mean time to treatment failure for mirabegron was 143 days versus 69 days for antimuscarinic drugs, although the observed adherence and persistence with treatment were similar.[22]

Mirabegron was generally well-tolerated for time periods of up to 52 weeks in adults with OAB in the pivotal clinical trials, with a tolerability profile consistent with that observed at 12 weeks.[13],[18],[19],[20] Mirabegron had a similar tolerability profile to placebo, with treatment-related AEs recorded in <20% of patients, being rarely serious (≤1% of patients), and leading to treatment discontinuation in <3% of patients.[37] The AEs in this sub-analysis was less than the AEs in the European analysis (23.7% vs. 42.8%), and so were mirabegron-related AEs (6.2% vs. 21%) and mirabegron-related AEs leading to permanent drug discontinuation (6.2% vs. 14%),[17] which were though similar to those of the 52-week randomized trial.[17],[20]

According to a meta-analysis, mirabegron appears to be better tolerated than antimuscarinic agents with regard to adverse reactions, such as dry mouth, constipation, and urinary retention.[38] In particular, dry mouth, the most frequently observed adverse reaction and the main AE leading to discontinuation of treatment with antimuscarinics,[39] did not occur at all in our sub-analysis, while it occurred in a very small percentage (0.6%) of the European participants overall.[17]

The limitations identified in the BELIEVE study[17] also apply for this sub-analysis. These include the absence of randomization, as well as the absence of a comparator arm to compare mirabegron with other oral pharmacological treatments, both representing bias points. In addition, the study results may have been influenced by differences in patient's interpretation and understanding of the questionnaires used, depending on the educational background. Nevertheless, it is presumed that we have obtained meaningful information regarding symptom bother and QoL, given that patients were followed up regardless of the treatment they were on throughout the 12-month observation period, and at the same time, patient-reported outcomes in routine clinical practice have been evaluated.


  Conclusions Top


The subanalysis in the Greek population confirmed the European results of the BELIEVE study. Patients receiving mirabegron in a real-world setting experienced clinically meaningful improvements in HRQoL. Mirabegron demonstrated a high persistence rate (72%) at 12 months (FAS population) and good tolerability, as no unexpected safety issues were observed and only a small percentage (6.2%) of drug-related AEs led to treatment discontinuation. In conclusion, the overall improvement in HRQoL, particularly in the population continuing to receive mirabegron at 10–12 months, as well as the low incidence of adverse events, may have contributed to the high persistence rate.

Acknowledgments

The authors would like to thank the BELIEVE study investigators, and all Greek patients and their parents/legal representatives who took part in the study.

Financial support and sponsorship

This study was funded by Astellas Pharma Europe B.V. Medical writing support was provided by Sofia Poulou InSciSol – Integrated Scientific Solutions and funded by Astellas Pharmaceuticals A.E.B.E.

Conflict of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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